TY - JOUR AU - Bartók, Ádám AU - Csanády, László TI - TRPM2 - an adjustable thermostat JF - CELL CALCIUM J2 - CELL CALCIUM VL - 118 PY - 2024 PG - 6 SN - 0143-4160 DO - 10.1016/j.ceca.2024.102850 UR - https://m2.mtmt.hu/api/publication/34502176 ID - 34502176 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László TI - Towards personalized medicine for cystic fibrosis patients with rare mutations JF - JOURNAL OF PHYSIOLOGY-LONDON J2 - J PHYSIOL-LONDON VL - 602 PY - 2024 IS - 2 SP - 257 EP - 258 PG - 2 SN - 0022-3751 DO - 10.1113/JP286135 UR - https://m2.mtmt.hu/api/publication/34507016 ID - 34507016 LA - English DB - MTMT ER - TY - CHAP AU - Csanády, László ED - Mandl, József ED - Csala, Miklós TI - Cystás fibrosis T2 - Orvosi patobiokémia PB - Medicina Könyvkiadó Zrt. CY - Budapest SN - 9789632267821 PY - 2023 SP - 307 EP - 310 PG - 4 UR - https://m2.mtmt.hu/api/publication/34722662 ID - 34722662 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Csanády, László TI - Blue flash sheds light on the roles of individual phosphoserines in CFTR channel activation JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 155 PY - 2023 IS - 6 PG - 3 SN - 0022-1295 DO - 10.1085/jgp.202313336 UR - https://m2.mtmt.hu/api/publication/33755807 ID - 33755807 N1 - Department of Biochemistry, Semmelweis University, Budapest, Hungary HCEMM-SE Molecular Channelopathies Research Group, Budapest, Hungary ELKH-SE Ion Channel Research Group, Budapest, Hungary Export Date: 31 August 2023 CODEN: JEMEA Correspondence Address: Csanády, L.; Department of Biochemistry, Hungary; email: csanady.laszlo@med.semmelweis-univ.hu Chemicals/CAS: cyclic AMP, 60-92-4; cystic fibrosis transmembrane conductance regulator, 126880-72-6; phosphoserine, 407-41-0; serine, 56-45-1, 6898-95-9; Cystic Fibrosis Transmembrane Conductance Regulator; Phosphoserine; Serine Funding details: 739593 Funding details: Cystic Fibrosis Foundation, CFF, CSANAD21G0 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, 144199 Funding text 1: This work was supported by EU Horizon 2020 Research and Innovation Program grant 739593, Cystic Fibrosis Foundation Research Grant CSANAD21G0, and Nemzeti Kutatási Fejlesztési és Innovációs Hivatal KKP_22 grant 144199 to L. Csanády. The author declares no competing financial interests. LA - English DB - MTMT ER - TY - JOUR AU - Simon, Márton AU - Csanády, László TI - Optimization of CFTR gating through the evolution of its extracellular loops JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 155 PY - 2023 IS - 4 PG - 16 SN - 0022-1295 DO - 10.1085/jgp.202213264 UR - https://m2.mtmt.hu/api/publication/33636409 ID - 33636409 LA - English DB - MTMT ER - TY - JOUR AU - Simon, Márton AU - Iordanov, Iordan AU - Szöllősi, András AU - Csanády, László TI - Estimating the true stability of the prehydrolytic outward-facing state in an ABC protein. JF - ELIFE J2 - ELIFE VL - 12 PY - 2023 PG - 19 SN - 2050-084X DO - 10.7554/eLife.90736 UR - https://m2.mtmt.hu/api/publication/34232792 ID - 34232792 AB - CFTR, the anion channel mutated in cystic fibrosis patients, is a model ABC protein whose ATP-driven conformational cycle is observable at single-molecule level in patch-clamp recordings. Bursts of CFTR pore openings are coupled to tight dimerization of its two nucleotide-binding domains (NBDs) and in wild-type (WT) channels are mostly terminated by ATP hydrolysis. The slow rate of non-hydrolytic closure - which determines how tightly bursts and ATP hydrolysis are coupled - is unknown, as burst durations of catalytic site mutants span a range of ~200-fold. Here, we show that Walker A mutation K1250A, Walker B mutation D1370N, and catalytic glutamate mutations E1371S and E1371Q all completely disrupt ATP hydrolysis. True non-hydrolytic closing rate of WT CFTR approximates that of K1250A and E1371S. That rate is slowed ~15-fold in E1371Q by a non-native inter-NBD H-bond, and accelerated ~15-fold in D1370N. These findings uncover unique features of the NBD interface in human CFTR. LA - English DB - MTMT ER - TY - JOUR AU - Bartók, Ádám AU - Csanády, László TI - Dual amplification strategy turns TRPM2 channels into supersensitive central heat detectors JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 119 PY - 2022 IS - 48 PG - 11 SN - 0027-8424 DO - 10.1073/pnas.2212378119 UR - https://m2.mtmt.hu/api/publication/33262968 ID - 33262968 N1 - Hungarian Centre of Excellence for Molecular Medicine-Semmelweis Egyetem (HCEMM-SE), Molecular Channelopathies Research Group, Semmelweis University, Budapest, H-1094, Hungary Magyar Tudományos Akadémia-Semmelweis Egyetem (MTA-SE), Ion Channel Research Group, Semmelweis University, Budapest, H-1094, Hungary Department of Biochemistry, Semmelweis University, Budapest, H-1094, Hungary Cited By :3 Export Date: 4 September 2023 CODEN: PNASA Correspondence Address: Csanády, L.; Hungarian Centre of Excellence for Molecular Medicine-Semmelweis Egyetem (HCEMM-SE), Hungary; email: csanady.laszlo@med.semmelweis-univ.hu Chemicals/CAS: adenosine diphosphate ribose, 20762-30-5; calcium ion, 14127-61-8; hydrogen peroxide, 7722-84-1; calcium, 7440-70-2, 14092-94-5; Adenosine Diphosphate Ribose; Calcium; Hydrogen Peroxide; TRPM Cation Channels Funding details: 739593 Funding details: GINOP-2.3.2-15-2016-00051 Funding details: ÚNKP-20-5-SE-6, ÚNKP-21-5-SE-10 Funding details: Magyar Tudományos Akadémia, MTA, BO/00103/20, LP2017-14/2017 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH Funding text 1: We thank Beáta Töröcsik for subcloning T5L-TRPM2 into pcDNA3, Iordan Iordanov for providing purified nvNUDT9H, and Katalin Zboray (Agricultural Institute, Centre for Agricultural Research, Martonvásár, Hungary) for providing the stable T5L TRPM2 cell line (Economic Development and Innovation Operational Programme (GINOP-2.3.2-15-2016-00051) of the National Research, Development and Innovation Office). Support was provided by EU Horizon 2020 Research and Innovation Program grant 739593 and MTA Lendület grant LP2017-14/2017 to L.C. and a New National Excellence Program (ÚNKP) award of the Ministry of Human Capacities of Hungary to Semmelweis University. Á.B. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00103/20) and the New National Excellence Program (ÚNKP) Bolyai+ scholarship of the Ministry of Human Capacities of Hungary (ÚNKP-20-5-SE-6 and ÚNKP-21-5-SE-10). Funding text 2: ACKNOWLEDGMENTS. We thank Beáta Töröcsik for subcloning T5L-TRPM2 into pcDNA3, Iordan Iordanov for providing purified nvNUDT9H, and Katalin Zboray (Agricultural Institute, Centre for Agricultural Research, Martonvásár, Hungary) for providing the stableT5LTRPM2 cell line (Economic Development and Innovation Operational Programme (GINOP-2.3.2-15-2016-00051) of the National Research, Development and Innovation Office). Support was provided by EU Horizon 2020 Research and Innovation Program grant 739593 and MTA Lendület grant LP2017-14/2017 to L.C. and a New National Excellence Program (ÚNKP) award of the Ministry of Human Capacities of Hungary to Semmelweis University. Á.B. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00103/20) and the New National Excellence Program (ÚNKP) Bolyai+ scholarship of the Ministry of Human Capacities of Hungary (ÚNKP-20-5-SE-6 and ÚNKP-21-5-SE-10). AB - The Ca 2+ and ADP ribose (ADPR)-activated cation channel TRPM2 is the closest homolog of the cold sensor TRPM8 but serves as a deep-brain warmth sensor. To unravel the molecular mechanism of heat sensing by the TRPM2 protein, we study here temperature dependence of TRPM2 currents in cell-free membrane patches across ranges of agonist concentrations. We find that channel gating remains strictly agonist-dependent even at 40°C: heating alone or in combination with just Ca 2+ , just ADPR, Ca 2+ + cyclic ADPR, or H 2 O 2 pretreatment only marginally activates TRPM2. For fully liganded TRPM2, pore opening is intrinsically endothermic, due to ~10-fold larger activation enthalpy for opening (~200 kJ/mol) than for closure (~20 kJ/mol). However, the temperature threshold is too high (>40°C) for unliganded but too low (<15°C) for fully liganded channels. Thus, warmth sensitivity around 37°C is restricted to narrow ranges of agonist concentrations. For ADPR, that range matches, but for Ca 2+ , it exceeds bulk cytosolic values. The supraphysiological [Ca 2+ ] needed for TRPM2 warmth sensitivity is provided by Ca 2+ entering through the channel’s pore. That positive feedback provides further strong amplification to the TRPM2 temperature response (Q 10 ~ 1,000), enabling the TRPM2 protein to autonomously respond to tiny temperature fluctuations around 37°C. These functional data together with published structures suggest a molecular mechanism for opposite temperature dependences of two closely related channel proteins. LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László TI - Degenerate but indispensable: How CFTR channel activity depends on the catalytically inactive ATP binding site JF - JOURNAL OF PHYSIOLOGY-LONDON J2 - J PHYSIOL-LONDON VL - 599 PY - 2021 IS - 20 SP - 4523 EP - 4524 PG - 2 SN - 0022-3751 DO - 10.1113/JP282278 UR - https://m2.mtmt.hu/api/publication/32358289 ID - 32358289 LA - English DB - MTMT ER - TY - JOUR AU - Simon, Márton AU - Csanády, László TI - Molecular pathology of the R117H cystic fibrosis mutation is explained by loss of a hydrogen bond JF - ELIFE J2 - ELIFE VL - 10 PY - 2021 PG - 19 SN - 2050-084X DO - 10.7554/eLife.74693 UR - https://m2.mtmt.hu/api/publication/32573094 ID - 32573094 AB - The phosphorylation-activated anion channel cystic fibrosis transmembrane conductance regulator (CFTR) is gated by an ATP hydrolysis cycle at its two cytosolic nucleotide-binding domains, and is essential for epithelial salt-water transport. A large number of CFTR mutations cause cystic fibrosis. Since recent breakthrough in targeted pharmacotherapy, CFTR mutants with impaired gating are candidates for stimulation by potentiator drugs. Thus, understanding the molecular pathology of individual mutations has become important. The relatively common R117H mutation affects an extracellular loop, but nevertheless causes a strong gating defect. Here, we identify a hydrogen bond between the side chain of arginine 117 and the backbone carbonyl group of glutamate 1124 in the cryo-electronmicroscopic structure of phosphorylated, ATP-bound CFTR. We address the functional relevance of that interaction for CFTR gating using macroscopic and microscopic inside-out patch-clamp recordings. Employing thermodynamic double-mutant cycles, we systematically track gating-state-dependent changes in the strength of the R117-E1124 interaction. We find that the H-bond is formed only in the open state, but neither in the short-lived 'flickery' nor in the long-lived 'interburst' closed state. Loss of this H-bond explains the strong gating phenotype of the R117H mutant, including robustly shortened burst durations and strongly reduced intraburst open probability. The findings may help targeted potentiator design. LA - English DB - MTMT ER - TY - JOUR AU - Mihályi, Csaba AU - Iordanov, Iordan AU - Törőcsik, Beáta AU - Csanády, László TI - Simple binding of protein kinase A, prior to phosphorylation, allows CFTR anion channels to be opened by nucleotides JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 117 PY - 2020 IS - 35 SP - 21740 EP - 21746 PG - 7 SN - 0027-8424 DO - 10.1073/pnas.2007910117 UR - https://m2.mtmt.hu/api/publication/31397038 ID - 31397038 LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Balázs AU - Iordanov, Iordan AU - Csanády, László TI - Selective profiling of N- And C-terminal nucleotide-binding sites in a TRPM2 channel JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 152 PY - 2020 IS - 5 PG - 13 SN - 0022-1295 DO - 10.1085/jgp.201912533 UR - https://m2.mtmt.hu/api/publication/31365406 ID - 31365406 N1 - Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary MTA-SE Lendület Ion Channel Research Group, Semmelweis University, Budapest, Hungary Cited By :7 Export Date: 15 September 2021 CODEN: JGPLA Correspondence Address: Tóth, B.; Department of Medical Biochemistry, Hungary; email: toth.balazs@med.semmelweis-univ.hu Chemicals/CAS: adenosine diphosphate ribose, 20762-30-5; amino acid, 65072-01-7; calcium, 7440-70-2, 14092-94-5; Adenosine Diphosphate Ribose; Amino Acids; Calcium; Ligands; Nucleotides; TRPM Cation Channels; TRPM2 protein, human Funding details: Semmelweis Egyetem, 18-4-SE-132, 19-4-SE-49 Funding details: Magyar Tudományos Akadémia, MTA, LP2017-14/2017 Funding text 1: Supported by the Hungarian Academy of Sciences (Lendület grant LP2017-14/2017 to L. Csanády) and a Ministry of Human Capacities of Hungary New National Excellence Program (Új Nemzeti Kiválóság Program) award to Semmelweis University. B. Tóth is a János Bolyai Research Fellow, supported by postdoctoral Új Nemzeti Kiválóság Program grants 18-4-SE-132 and 19-4-SE-49. The authors declare no competing financial interests. AB - Transient receptor potential melastatin 2 (TRPM2) is a homotetrameric Ca2+-permeable cation channel important for the immune response, body temperature regulation, and insulin secretion, and is activated by cytosolic Ca2+ and ADP ribose (ADPR). ADPR binds to two distinct locations, formed by large N- and C-terminal cytosolic domains, respectively, of the channel protein. In invertebrate TRPM2 channels, the C-terminal site is not required for channel activity but acts as an active ADPR phosphohydrolase that cleaves the activating ligand. In vertebrate TRPM2 channels, the C-terminal site is catalytically inactive but cooperates with the N-terminal site in channel activation. The precise functional contributions to channel gating and the nucleotide selectivities of the two sites in various species have not yet been deciphered. For TRPM2 of the sea anemone Nematostella vectensis (nvTRPM2), catalytic activity is solely attributable to the C-terminal site. Here, we show that nvTRPM2 channel gating properties remain unaltered upon deletion of the C-terminal domain, indicating that the N-terminal site is single-handedly responsible for channel gating. Exploiting such functional independence of the N- and C-terminal sites, we selectively measure their affinity profiles for a series of ADPR analogues, as reflected by apparent affinities for channel activation and catalysis, respectively. Using site-directed mutagenesis, we confirm that the same N-terminal site observed in vertebrate TRPM2 channels was already present in ancient cnidarians. Finally, by characterizing the functional effects of six amino acid side chain truncations in the N-terminal site, we provide first insights into the mechanistic contributions of those side chains to TRPM2 channel gating. © 2020 Tóth et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Törőcsik, Beáta TI - Cystic fibrosis drug ivacaftor stimulates CFTR channels at picomolar concentrations JF - ELIFE J2 - ELIFE VL - 8 PY - 2019 PG - 18 SN - 2050-084X DO - 10.7554/eLife.46450 UR - https://m2.mtmt.hu/api/publication/30775333 ID - 30775333 AB - The devastating inherited disease cystic fibrosis (CF) is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel. The recent approval of the CFTR potentiator drug ivacaftor (Vx-770) for the treatment of CF patients has marked the advent of causative CF therapy. Currently, thousands of patients are being treated with the drug, and its molecular mechanism of action is under intensive investigation. Here we determine the solubility profile and true stimulatory potency of Vx-770 towards wild-type (WT) and mutant human CFTR channels in cell-free patches of membrane. We find that its aqueous solubility is ~200 fold lower (~60 nanomolar), whereas the potency of its stimulatory effect is >100 fold higher, than reported, and is unexpectedly fully reversible. Strong, but greatly delayed, channel activation by picomolar Vx-770 identifies multiple sequential slow steps in the activation pathway. These findings provide solid guidelines for the design of in vitro studies using Vx-770. © 2019, Csanády and Töröcsik. LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Vergani, Paola AU - Gadsby, David C TI - STRUCTURE, GATING, AND REGULATION OF THE CFTR ANION CHANNEL. JF - PHYSIOLOGICAL REVIEWS J2 - PHYSIOL REV VL - 99 PY - 2019 IS - 1 SP - 707 EP - 738 PG - 32 SN - 0031-9333 DO - 10.1152/physrev.00007.2018 UR - https://m2.mtmt.hu/api/publication/30387986 ID - 30387986 N1 - Department of Medical Biochemistry, Semmelweis UniversityBudapest, Hungary MTA-SE Ion Channel Research GroupBudapest, Hungary Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, NY, United States Cited By :24 Export Date: 2 July 2020 CODEN: PHREA Chemicals/CAS: adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; cyclic AMP dependent protein kinase; cystic fibrosis transmembrane conductance regulator, 126880-72-6; Adenosine Triphosphate; Anions; Cystic Fibrosis Transmembrane Conductance Regulator Funding details: Cystic Fibrosis Trust, CF Funding text 1: Supported by Cystic Fibrosis Trust Project no. SRC 005 and Sparks Grant reference no. 15UCL04 (to P. Vergani), and Hungarian Academy of Sciences Lendület Grant LP2017–14/2017 and Cystic Fibrosis Foundation Research Grant CSANAD17G0 (to L. Csanády). Department of Medical Biochemistry, Semmelweis UniversityBudapest, Hungary MTA-SE Ion Channel Research GroupBudapest, Hungary Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, NY, United States Cited By :60 Export Date: 11 August 2021 CODEN: PHREA Funding Agency and Grant Number: Cystic Fibrosis Trust [SRC 005]; Sparks Grant [15UCL04]; Hungarian Academy of Sciences Lendulet Grant [LP2017-14/2017]; Cystic Fibrosis Foundation Research Grant [CSANAD17G0] Funding text: Supported by Cystic Fibrosis Trust Project no. SRC 005 and Sparks Grant reference no. 15UCL04 (to P. Vergani), and Hungarian Academy of Sciences Lendulet Grant LP2017-14/2017 and Cystic Fibrosis Foundation Research Grant CSANAD17G0 (to L. Csanady). Department of Medical Biochemistry, Semmelweis UniversityBudapest, Hungary MTA-SE Ion Channel Research GroupBudapest, Hungary Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, NY, United States Cited By :60 Export Date: 30 August 2021 CODEN: PHREA Department of Medical Biochemistry, Semmelweis UniversityBudapest, Hungary MTA-SE Ion Channel Research GroupBudapest, Hungary Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, NY, United States Cited By :60 Export Date: 31 August 2021 CODEN: PHREA AB - The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the ATP binding cassette (ABC) transporter superfamily but functions as an anion channel crucial for salt and water transport across epithelial cells. CFTR dysfunction, because of mutations, causes cystic fibrosis (CF). The anion-selective pore of the CFTR protein is formed by its two transmembrane domains (TMDs) and regulated by its cytosolic domains: two nucleotide binding domains (NBDs) and a regulatory (R) domain. Channel activation requires phosphorylation of the R domain by cAMP-dependent protein kinase (PKA), and pore opening and closing (gating) of phosphorylated channels is driven by ATP binding and hydrolysis at the NBDs. This review summarizes available information on structure and mechanism of the CFTR protein, with a particular focus on atomic-level insight gained from recent cryo-electron microscopic structures and on the molecular mechanisms of channel gating and its regulation. The pharmacological mechanisms of small molecules targeting CFTR's ion channel function, aimed at treating patients suffering from CF and other diseases, are briefly discussed. LA - English DB - MTMT ER - TY - JOUR AU - Iordanov, Iordan AU - Tóth, Balázs AU - Szöllősi, András AU - Csanády, László TI - Enzyme activity and selectivity filter stability of ancient TRPM2 channels were simultaneously lost in early vertebrates JF - ELIFE J2 - ELIFE VL - 8 PY - 2019 IS - 2019 PG - 23 SN - 2050-084X DO - 10.7554/eLife.44556 UR - https://m2.mtmt.hu/api/publication/30637149 ID - 30637149 N1 - Funding Agency and Grant Number: Howard Hughes Medical InstituteHoward Hughes Medical Institute; Magyar Tudomanyos Akademia [LP2017-14/2017]; Ministry of Human Capacities of Hungary [UNKP 17-4-I-SE-61, UNKP 18-4-SE-132]; Magyar Tudomanyos Akademia Funding text: Howard Hughes Medical Institute International Early Career Scientist Award Laszlo Csanady; Magyar Tudomanyos Akademia LP2017-14/2017 Laszlo Csanady; Ministry of Human Capacities of Hungary UNKP 17-4-I-SE-61 Balazs Toth; Magyar Tudomanyos Akademia Bolyai Research Fellowship Balazs Toth; Ministry of Human Capacities of Hungary UNKP-FIKP Laszlo Csanady; Ministry of Human Capacities of Hungary UNKP 18-4-SE-132 Balazs Toth; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Export Date: 7 January 2020 Correspondence Address: Csanády, L.; Department of Medical Biochemistry, Semmelweis UniversityHungary; email: csanady.laszlo@med.semmelweis-univ.hu Export Date: 8 January 2020 Correspondence Address: Csanády, L.; Department of Medical Biochemistry, Semmelweis UniversityHungary; email: csanady.laszlo@med.semmelweis-univ.hu AB - Transient Receptor Potential Melastatin 2 (TRPM2) is a cation channel important for the immune response, insulin secretion, and body temperature regulation. It is activated by cytosolic ADP ribose (ADPR) and contains a nudix-type motif 9 (NUDT9)-homology (NUDT9-H) domain homologous to ADPR phosphohydrolases (ADPRases). Human TRPM2 (hsTRPM2) is catalytically inactive due to mutations in the conserved Nudix box sequence. Here, we show that TRPM2 Nudix motifs are canonical in all invertebrates but vestigial in vertebrates. Correspondingly, TRPM2 of the cnidarian Nematostella vectensis (nvTRPM2) and the choanoflagellate Salpingoeca rosetta (srTRPM2) are active ADPRases. Disruption of ADPRase activity fails to affect nvTRPM2 channel currents, reporting a catalytic cycle uncoupled from gating. Furthermore, pore sequence substitutions responsible for inactivation of hsTRPM2 also appeared in vertebrates. Correspondingly, zebrafish (Danio rerio) TRPM2 (drTRPM2) and hsTRPM2 channels inactivate, but srTRPM2 and nvTRPM2 currents are stable. Thus, catalysis and pore stability were lost simultaneously in vertebrate TRPM2 channels. LA - English DB - MTMT ER - TY - JOUR AU - Martin, SL AU - Saint-Criq, V AU - Hwang, TC AU - Csanády, László TI - Ion channels as targets to treat cystic fibrosis lung disease JF - JOURNAL OF CYSTIC FIBROSIS J2 - J CYST FIBROS VL - 17 PY - 2018 IS - 2 SP - S22 EP - S27 PG - 6 SN - 1569-1993 DO - 10.1016/j.jcf.2017.10.006 UR - https://m2.mtmt.hu/api/publication/3287704 ID - 3287704 N1 - Cited By :4 Export Date: 9 September 2019 CODEN: JCFOA Correspondence Address: Martin, S.L.; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, United Kingdom; email: l.martin@qub.ac.uk Chemicals/CAS: cystic fibrosis transmembrane conductance regulator, 126880-72-6; Cystic Fibrosis Transmembrane Conductance Regulator Funding details: Transport Funding details: National Institutes of Health, R01DK55835 Funding details: Cystic Fibrosis Foundation, Hwang11P0, CSANAD17G0 Funding details: PJ552, PJ559 Funding details: Medical Research Council, INOVCF/SRC003, MC_PC_141113 Funding details: Invest Northern Ireland, POC600 Funding text 1: We acknowledge the support of the organising committee of the European Cystic Fibrosis Basic Science conference 2017 and the contributions that were also made by Drs Paolo Scudieri (Telethon Institute of Genetics and Medicine) and Génesis Vega (Centro de Estudios Cientificos, Valdivia, Chile) to Symposium 6 (Cell Physiology and Ion Transport) of the conference. SLM's work has received financial support from the CF Trust, UK (PJ552 and PJ559), Invest Northern Ireland (POC600) and the Medical Research Council (MC_PC_141113); VSC is currently funded by a Strategic Research Centre grant (INOVCF/SRC003) from the CF Trust UK; TCH by research grants from the NIH (R01DK55835) and Cystic Fibrosis Foundation (Hwang11P0) and LC by a Research Grant from the Cystic Fibrosis Foundation (CSANAD17G0). AB - Lung health relies on effective mucociliary clearance and innate immune defence mechanisms. In cystic fibrosis (CF), an imbalance in ion transport due to an absence of chloride ion secretion, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and a concomitant sodium hyperabsorption, caused by dyregulation of the epithelial sodium channel (ENaC), results in mucus stasis which predisposes the lungs to cycles of chronic infection and inflammation leading to lung function decline. An increased understanding of CFTR structure and function has provided opportunity for the development of a number of novel modulators targeting mutant CFTR however, it is important to also consider other ion channels and transporters present in the airways as putative targets for drug development. In this review, we discuss recent advances in CFTR biology which will contribute to further drug discovery in the field. We also examine developments to inhibit the epithelial sodium channel (ENaC) and potentially activate alternative chloride channels and transporters as a multi-tracked strategy to hydrate CF airways and restore normal mucociliary clearance mechanisms in a manner independent of CFTR mutation. LA - English DB - MTMT ER - TY - JOUR AU - Zhang, Zhe AU - Tóth, Balázs AU - Szöllősi, András AU - Chen, Jue AU - Csanády, László TI - Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation JF - ELIFE J2 - ELIFE VL - 7 PY - 2018 PG - 22 SN - 2050-084X DO - 10.7554/eLife.36409 UR - https://m2.mtmt.hu/api/publication/30465914 ID - 30465914 AB - Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel required for immune cell activation, insulin secretion, and body heat control. TRPM2 is activated by cytosolic Ca2+, phosphatidyl-inositol-4,5-bisphosphate and ADP ribose. Here, we present the 3 A resolution electron cryo-microscopic structure of TRPM2 from Nematostella vectensis, 63% similar in sequence to human TRPM2, in the Ca2+-bound closed state. Compared to other TRPM channels, TRPM2 exhibits unique structural features that correlate with its function. The pore is larger and more negatively charged, consistent with its high Ca2+ selectivity and larger conductance. The intracellular Ca2+ binding sites are connected to the pore and cytosol, explaining the unusual dependence of TRPM2 activity on intra- and extracellular Ca2+. In addition, the absence of a post filter motif is likely the cause of the rapid inactivation of human TRPM2. Together, our cryo-EM and electrophysiology studies provide a molecular understanding of the unique gating mechanism of TRPM2. LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László TI - CFTR gating: Invisible transitions made visible JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 149 PY - 2017 IS - 4 SP - 413 EP - 416 PG - 4 SN - 0022-1295 DO - 10.1085/jgp.201711777 UR - https://m2.mtmt.hu/api/publication/3211072 ID - 3211072 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László TI - Sensory neurons: A new target for G protein signaling JF - ELIFE J2 - ELIFE VL - 6 PY - 2017 PG - 4 SN - 2050-084X DO - 10.7554/eLife.31106 UR - https://m2.mtmt.hu/api/publication/3287390 ID - 3287390 AB - G protein-coupled receptor stimulation inhibits TRPM3 channel activity through direct binding of the Gβγ subunit to the channel. © Csanády. LA - English DB - MTMT ER - TY - JOUR AU - Liu, F AU - Zhang, Z AU - Csanády, László AU - Gadsby, DC AU - Chen, J TI - Molecular Structure of the Human CFTR Ion Channel JF - CELL J2 - CELL VL - 169 PY - 2017 IS - 1 SP - 85 EP - 95.e8 SN - 0092-8674 DO - 10.1016/j.cell.2017.02.024 UR - https://m2.mtmt.hu/api/publication/3210856 ID - 3210856 N1 - Cited By :244 Export Date: 9 March 2022 CODEN: CELLB Correspondence Address: Chen, J.; Laboratory of Membrane Biophysics and Biology, 1230 York Avenue, United States Chemicals/CAS: adenosine triphosphatase, 37289-25-1, 9000-83-3; adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; arginine, 1119-34-2, 15595-35-4, 7004-12-8, 74-79-3; cyclic AMP dependent protein kinase; cysteine, 4371-52-2, 52-89-1, 52-90-4; cystic fibrosis transmembrane conductance regulator, 126880-72-6; lysine, 56-87-1, 6899-06-5, 70-54-2; multidrug resistance associated protein 1; proline, 147-85-3, 7005-20-1; protein, 67254-75-5; serine, 56-45-1, 6898-95-9; Adenosine Triphosphate; CFTR protein, human; CFTR protein, zebrafish; Cystic Fibrosis Transmembrane Conductance Regulator; Zebrafish Proteins Funding details: LP2012-39/2012 Funding details: Howard Hughes Medical Institute, HHMI Funding details: Cystic Fibrosis Foundation, CFF, CSANAD15G0 Funding details: Rockefeller University Funding text 1: We thank Eric Gouaux for the expression vector, Mark Ebrahim and Johanna Sotiris at the Rockefeller Evelyn Gruss Lipper Cryo-Electron Microscopy Resource Center for assistance in data collection, and Sarah McCarry for editing this manuscript. This work is supported by the Rockefeller University (to J.C. and D.C.G), the Howard Hughes Medical Institute (to J.C.), and MTA-Momentum (LP2012-39/2012) and Cystic Fibrosis Foundation (CSANAD15G0) grants (to L.C.). AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that uniquely functions as an ion channel. Here, we present a 3.9 Å structure of dephosphorylated human CFTR without nucleotides, determined by electron cryomicroscopy (cryo-EM). Close resemblance of this human CFTR structure to zebrafish CFTR under identical conditions reinforces its relevance for understanding CFTR function. The human CFTR structure reveals a previously unresolved helix belonging to the R domain docked inside the intracellular vestibule, precluding channel opening. By analyzing the sigmoid time course of CFTR current activation, we propose that PKA phosphorylation of the R domain is enabled by its infrequent spontaneous disengagement, which also explains residual ATPase and gating activity of dephosphorylated CFTR. From comparison with MRP1, a feature distinguishing CFTR from all other ABC transporters is the helix-loop transition in transmembrane helix 8, which likely forms the structural basis for CFTR's channel function. © 2017 Elsevier Inc. LA - English DB - MTMT ER - TY - JOUR AU - Sorum, Ben AU - Törőcsik, Beáta AU - Csanády, László TI - Asymmetry of movements in CFTR's two ATP sites during pore opening serves their distinct functions JF - ELIFE J2 - ELIFE VL - 6 PY - 2017 PG - 17 SN - 2050-084X DO - 10.7554/eLife.29013 UR - https://m2.mtmt.hu/api/publication/3287727 ID - 3287727 AB - CFTR, the chloride channel mutated in cystic fibrosis (CF) patients, is opened by ATP binding to two cytosolic nucleotide binding domains (NBDs), but pore-domain mutations may also impair gating. ATP-bound NBDs dimerize occluding two nucleotides at interfacial binding sites; one site hydrolyzes ATP, the other is inactive. The pore opens upon tightening, and closes upon disengagement, of the catalytic site following ATP hydrolysis. Extent, timing, and role of non-catalytic-site movements are unknown. Here we exploit equilibrium gating of a hydrolysis-deficient mutant and apply Phi value analysis to compare timing of opening-associated movements at multiple locations, from the cytoplasmic ATP sites to the extracellular surface. Marked asynchrony of motion in the two ATP sites reveals their distinct roles in channel gating. The results clarify the molecular mechanisms of functional cross-talk between canonical and degenerate ATP sites in asymmetric ABC proteins, and of the gating defects caused by two common CF mutations. LA - English DB - MTMT ER - TY - JOUR AU - Mészáros-Bársony, Orsolya AU - Szalóki, Gábor AU - Türk, Dóra AU - Tarapcsák, Szabolcs AU - Gutay-Tóth, Zsuzsanna AU - Bacsó, Zsolt AU - Holb, Imre AU - Székvölgyi, Lóránt AU - Szabó, Gábor AU - Csanády, László AU - Szakács, Gergely AU - Kormosné, Goda Katalin TI - A single active catalytic site is sufficient to promote transport in P-glycoprotein JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 6 PY - 2016 PG - 16 SN - 2045-2322 DO - 10.1038/srep24810 UR - https://m2.mtmt.hu/api/publication/3057146 ID - 3057146 AB - P-glycoprotein (Pgp) is an ABC transporter responsible for the ATP-dependent efflux of chemotherapeutic compounds from multidrug resistant cancer cells. Better understanding of the molecular mechanism of Pgp-mediated transport could promote rational drug design to circumvent multidrug resistance. By measuring drug binding affinity and reactivity to a conformation-sensitive antibody we show here that nucleotide binding drives Pgp from a high to a low substrate-affinity state and this switch coincides with the flip from the inward- to the outward-facing conformation. Furthermore, the outward-facing conformation survives ATP hydrolysis: the post-hydrolytic complex is stabilized by vanadate, and the slow recovery from this state requires two functional catalytic sites. The catalytically inactive double Walker A mutant is stabilized in a high substrate affinity inward-open conformation, but mutants with one intact catalytic center preserve their ability to hydrolyze ATP and to promote drug transport, suggesting that the two catalytic sites are randomly recruited for ATP hydrolysis. LA - English DB - MTMT ER - TY - JOUR AU - Iordanov, Iordan AU - Mihályi, Csaba AU - Tóth, Balázs AU - Csanády, László TI - The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity JF - ELIFE J2 - ELIFE VL - 5 PY - 2016 PG - 20 SN - 2050-084X DO - 10.7554/eLife.17600 UR - https://m2.mtmt.hu/api/publication/3105008 ID - 3105008 N1 - Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary MTA-SE Ion Channel Research Group, Semmelweis University, Budapest, Hungary Cited By :17 Export Date: 20 September 2019 Correspondence Address: Csanády, L.; Department of Medical Biochemistry, Semmelweis UniversityHungary; email: csanady.laszlo@med.semmelweis-univ.hu Funding Agency and Grant Number: Howard Hughes Medical Institute International Early Career Scientist [55007416]; Magyar Tudomanyos Akademia Lendulet [LP2012-39/2012] Funding text: Howard Hughes Medical Institute International Early Career Scientist grant, 55007416 Laszlo Csanady; Magyar Tudomanyos Akademia Lendulet grant, LP2012-39/2012 Laszlo Csanady Export Date: 7 January 2020 Correspondence Address: Csanády, L.; Department of Medical Biochemistry, Semmelweis UniversityHungary; email: csanady.laszlo@med.semmelweis-univ.hu LA - English DB - MTMT ER - TY - JOUR AU - Mihályi, Csaba AU - Törőcsik, Beáta AU - Csanády, László TI - Obligate coupling of CFTR pore opening to tight nucleotide-binding domain dimerization JF - ELIFE J2 - ELIFE VL - 5 PY - 2016 PG - 12 SN - 2050-084X DO - 10.7554/eLife.18164 UR - https://m2.mtmt.hu/api/publication/3083629 ID - 3083629 AB - In CFTR, the chloride channel mutated in cystic fibrosis (CF) patients, ATP-binding-induced dimerization of two cytosolic nucleotide binding domains (NBDs) opens the pore, and dimer disruption following ATP hydrolysis closes it. Spontaneous openings without ATP are rare in wild-type CFTR, but in certain CF mutants constitute the only gating mechanism, stimulated by ivacaftor, a clinically approved CFTR potentiator. The molecular motions underlying spontaneous gating are unclear. Here we correlate energetic coupling between residues across the dimer interface with spontaneous pore opening/closure in single CFTR channels. We show that spontaneous openings are also strictly coupled to NBD dimerization, which may therefore occur even without ATP. Coordinated NBD/pore movements are therefore intrinsic to CFTR: ATP alters the stability, but not the fundamental structural architecture, of open- and closed-pore conformations. This explains correlated effects of phosphorylation, mutations, and drugs on ATP-driven and spontaneous activity, providing insights for understanding CF mutation and drug mechanisms. LA - English DB - MTMT ER - TY - JOUR AU - Sorum, Ben AU - Czégé, Dávid AU - Csanády, László TI - Timing of CFTR Pore Opening and Structure of Its Transition State. JF - CELL J2 - CELL VL - 163 PY - 2015 IS - 3 SP - 724 EP - 733 PG - 10 SN - 0092-8674 DO - 10.1016/j.cell.2015.09.052 UR - https://m2.mtmt.hu/api/publication/2964742 ID - 2964742 AB - In CFTR, the chloride ion channel mutated in cystic fibrosis (CF) patients, pore opening is coupled to ATP-binding-induced dimerization of two cytosolic nucleotide binding domains (NBDs) and closure to dimer disruption following ATP hydrolysis. CFTR opening rate, unusually slow because of its high-energy transition state, is further slowed by CF mutation DeltaF508. Here, we exploit equilibrium gating of hydrolysis-deficient CFTR mutant D1370N and apply rate-equilibrium free-energy relationship analysis to estimate relative timing of opening movements in distinct protein regions. We find clear directionality of motion along the longitudinal protein axis and identify an opening transition-state structure with the NBD dimer formed but the pore still closed. Thus, strain at the NBD/pore-domain interface, the DeltaF508 mutation locus, underlies the energetic barrier for opening. Our findings suggest a therapeutic opportunity to stabilize this transition-state structure pharmacologically in DeltaF508-CFTR to correct its opening defect, an essential step toward restoring CFTR function. LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Balázs AU - Iordanov, Iordan AU - Csanády, László TI - Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2'-phosphate JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 145 PY - 2015 IS - 5 SP - 419 EP - 430 PG - 12 SN - 0022-1295 DO - 10.1085/jgp.201511377 UR - https://m2.mtmt.hu/api/publication/2949645 ID - 2949645 N1 - Funding Agency and Grant Number: International Early Career Scientist grant from the Howard Hughes Medical InstituteHoward Hughes Medical Institute; MTA Lendulet grant [LP2012-39/2012] Funding text: This work is supported by an International Early Career Scientist grant from the Howard Hughes Medical Institute to L. Csanady, and MTA Lendulet grant LP2012-39/2012. Export Date: 7 January 2020 CODEN: JGPLA Correspondence Address: Csanády, L.; Department of Medical Biochemistry, Semmelweis UniversityHungary; email: csanay.laszlo@med.semmelweis-univ.hu AB - Transient receptor potential melastatin 2 (TRPM2), a Ca(2+)-permeable cation channel implicated in postischemic neuronal cell death, leukocyte activation, and insulin secretion, is activated by intracellular ADP ribose (ADPR). In addition, the pyridine dinucleotides nicotinamide-adenine-dinucleotide (NAD), nicotinic acid-adenine-dinucleotide (NAAD), and NAAD-2'-phosphate (NAADP) have been shown to activate TRPM2, or to enhance its activation by ADPR, when dialyzed into cells. The precise subset of nucleotides that act directly on the TRPM2 protein, however, is unknown. Here, we use a heterologously expressed, affinity-purified-specific ADPR hydrolase to purify commercial preparations of pyridine dinucleotides from substantial contaminations by ADPR or ADPR-2'-phosphate (ADPRP). Direct application of purified NAD, NAAD, or NAADP to the cytosolic face of TRPM2 channels in inside-out patches demonstrated that none of them stimulates gating, or affects channel activation by ADPR, indicating that none of these dinucleotides directly binds to TRPM2. Instead, our experiments identify for the first time ADPRP as a true direct TRPM2 agonist of potential biological interest. LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Törőcsik, Beáta TI - Structure-activity analysis of a CFTR channel potentiator: Distinct molecular parts underlie dual gating effects. JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 144 PY - 2014 IS - 4 SP - 321 EP - 336 PG - 16 SN - 0022-1295 DO - 10.1085/jgp.201411246 UR - https://m2.mtmt.hu/api/publication/2761953 ID - 2761953 AB - The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette transporter superfamily that functions as an epithelial chloride channel. Gating of the CFTR ion conduction pore involves a conserved irreversible cyclic mechanism driven by ATP binding and hydrolysis at two cytosolic nucleotide-binding domains (NBDs): formation of an intramolecular NBD dimer that occludes two ATP molecules opens the pore, whereas dimer disruption after ATP hydrolysis closes it. CFTR dysfunction resulting from inherited mutations causes CF. The most common CF mutation, deletion of phenylalanine 508 (DeltaF508), impairs both protein folding and processing and channel gating. Development of DeltaF508 CFTR correctors (to increase cell surface expression) and potentiators (to enhance open probability, Po) is therefore a key focus of CF research. The practical utility of 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB), one of the most efficacious potentiators of DeltaF508 CFTR identified to date, is limited by its pore-blocking side effect. NPPB-mediated stimulation of Po is unique in that it involves modulation of gating transition state stability. Although stabilization by NPPB of the transition state for pore opening enhances both the rate of channel opening and the very slow rate of nonhydrolytic closure, because of CFTR's cyclic gating mechanism, the net effect is Po stimulation. In addition, slowing of ATP hydrolysis by NPPB delays pore closure, further enhancing Po. Here we show that NPPB stimulates gating at a site outside the pore and that these individual actions of NPPB on CFTR are fully attributable to one or the other of its two complementary molecular parts, 3-nitrobenzoate (3NB) and 3-phenylpropylamine (3PP), both of which stimulate Po: the pore-blocking 3NB selectively stabilizes the transition state for opening, whereas the nonblocking 3PP selectively slows the ATP hydrolysis step. Understanding structure-activity relationships of NPPB might prove useful for designing potent, clinically relevant CFTR potentiators. LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Törőcsik, Beáta TI - Catalyst-like Modulation of Transitions States for CFTR Channel Opening and Closing: New Stimulation Strategy Exploits Nonequilibrium Gating JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 143 PY - 2014 IS - 2 SP - 269 EP - 287 PG - 19 SN - 0022-1295 DO - 10.1085/jgp.201311089 UR - https://m2.mtmt.hu/api/publication/2496247 ID - 2496247 LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Balázs AU - Iordanov, Iordan AU - Csanády, László TI - Putative chanzyme activity of TRPM2 cation channel is unrelated to pore gating JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 111 PY - 2014 IS - 47 SP - 16949 EP - 16954 PG - 6 SN - 0027-8424 DO - 10.1073/pnas.1412449111 UR - https://m2.mtmt.hu/api/publication/2762109 ID - 2762109 N1 - Funding Agency and Grant Number: Howard Hughes Medical InstituteHoward Hughes Medical Institute; MTA Lendulet Grant [LP2012-39/2012] Funding text: This work was supported by an International Early Career Scientist grant from the Howard Hughes Medical Institute (to L. C.) and MTA Lendulet Grant LP2012-39/2012. Department of Medical Biochemistry, Semmelweis University, Budapest, H-1094, Hungary Magyar Tudományos Akadémia - Semmelweis Egyetem Lendület (MTA-SE), Semmelweis University, Budapest, H-1094, Hungary Cited By :25 Export Date: 7 January 2020 CODEN: PNASA Correspondence Address: Csanády, L.; Department of Medical Biochemistry, Semmelweis UniversityHungary LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Mihályi, Csaba AU - Szöllősi, András AU - Törőcsik, Beáta AU - Vergani, P TI - Conformational changes in the catalytically inactive nucleotide-binding site of CFTR JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 142 PY - 2013 IS - 1 SP - 61 EP - 73 PG - 13 SN - 0022-1295 DO - 10.1085/jgp.201210954 UR - https://m2.mtmt.hu/api/publication/2333381 ID - 2333381 AB - A central step in the gating of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is the association of its two cytosolic nucleotide-binding domains (NBDs) into a head-to-tail dimer, with two nucleotides bound at the interface. Channel opening and closing, respectively, are coupled to formation and disruption of this tight NBD dimer. CFTR is an asymmetric adenosine triphosphate (ATP)-binding cassette protein in which the two interfacial-binding sites (composite sites 1 and 2) are functionally different. During gating, the canonical, catalytically active nucleotide-binding site (site 2) cycles between dimerized prehydrolytic (state O1), dimerized post-hydrolytic (state O2), and dissociated (state C) forms in a preferential C-->O1-->O2-->C sequence. In contrast, the catalytically inactive nucleotide-binding site (site 1) is believed to remain associated, ATP-bound, for several gating cycles. Here, we have examined the possibility of conformational changes in site 1 during gating, by studying gating effects of perturbations in site 1.Previous work showed that channel closure is slowed, both under hydrolytic and nonhydrolytic conditions, by occupancy of site 1 by N6-(2-phenylethyl)-ATP (P-ATP) as well as by the site-1 mutation H1348A (NBD2 signature sequence). Here, we found that P-ATP prolongs wild-type (WT) CFTR burst durations by selectively slowing (>2x) transition O1-->O2 and decreases the nonhydrolytic closing rate (transition O1-->C) of CFTR mutants K1250A ( approximately 4x) and E1371S ( approximately 3x). Mutation H1348A also slowed ( approximately 3x) the O1-->O2 transition in the WT background and decreased the nonhydrolytic closing rate of both K1250A ( approximately 3x) and E1371S ( approximately 3x) background mutants. Neither P-ATP nor the H1348A mutation affected the 1:1 stoichiometry between ATP occlusion and channel burst events characteristic to WT CFTR gating in ATP. The marked effect that different structural perturbations at site 1 have on both steps O1-->C and O1-->O2 suggests that the overall conformational changes that CFTR undergoes upon opening and coincident with hydrolysis at the active site 2 include significant structural rearrangement at site 1. LA - English DB - MTMT ER - TY - CHAP AU - Vergani, P AU - Gadsby, DC AU - Csanády, László ED - Roberts, Gordon TI - CFTR, an Ion Channel Evolved from ABC Transporter T2 - Encyclopedia of Biophysics PB - Springer Netherlands CY - Berlin CY - Heidelberg SN - 9783642167119 PY - 2013 SP - 254 EP - 265 PG - 12 DO - 10.1007/978-3-642-16712-6_364 UR - https://m2.mtmt.hu/api/publication/2221309 ID - 2221309 LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Balázs AU - Csanády, László TI - Pore collapse underlies irreversible inactivation of TRPM2 cation channel currents. JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 109 PY - 2012 IS - 33 SP - 13440 EP - 13445 PG - 6 SN - 0027-8424 DO - 10.1073/pnas.1204702109 UR - https://m2.mtmt.hu/api/publication/2041974 ID - 2041974 N1 - Funding Agency and Grant Number: Orszagos Tudomanyos Kutatasi Alapprogramok Grant [F 68143]; Howard Hughes Medical InstituteHoward Hughes Medical Institute Funding text: We thank Dorottya Mayer for oocyte isolation and injection; Tibor Rohacs for the TRPM8 clone, for PIP2, and for much valuable advice; and David Gadsby for discussions. L. C. is a Bolyai Research Fellow of the Hungarian Academy of Sciences. Support for this work was provided by Orszagos Tudomanyos Kutatasi Alapprogramok Grant F 68143 (to L. C.) and an International Early Career Scientist grant from the Howard Hughes Medical Institute (to L.C.). Cited By :33 Export Date: 7 January 2020 CODEN: PNASA Correspondence Address: Csanády, L.; Department of Medical Biochemistry, Semmelweis University, Budapest H-1094, Hungary; email: csanady.laszlo@med.semmelweis-univ.hu AB - The Ca(2+)-permeable cation channel transient receptor potential melastatin 2 (TRPM2) plays a key role in pathogen-evoked phagocyte activation, postischemic neuronal apoptosis, and glucose-evoked insulin secretion, by linking these cellular responses to oxidative stress. TRPM2 channels are coactivated by binding of intracellular ADP ribose and Ca(2+) to distinct cytosolically accessible sites on the channels. These ligands likely regulate the activation gate, conserved in the voltage-gated cation channel superfamily, that comprises a helix bundle formed by the intracellular ends of transmembrane helix six of each subunit. For several K(+) and TRPM family channels, activation gate opening requires the presence of phosphatidylinositol-bisphosphate (PIP(2)) in the inner membrane leaflet. Most TRPM family channels inactivate upon prolonged stimulation in inside-out patches; this "rundown" is due to PIP(2) depletion. TRPM2 currents also run down within minutes, but the molecular mechanism of this process is unknown. Here we report that high-affinity PIP(2) binding regulates Ca(2+) sensitivity of TRPM2 activation. Nevertheless, TRPM2 inactivation is not due to PIP(2) depletion; rather, it is state dependent, sensitive to permeating ions, and can be completely prevented by mutations in the extracellular selectivity filter. Introduction of two negative charges plus a single-residue insertion, to mimic the filter sequence of TRPM5, results in TRPM2 channels that maintain unabated maximal activity for over 1 h, and display altered permeation properties but intact ADP ribose/Ca(2+)-dependent gating. Thus, upon prolonged stimulation, the TRPM2 selectivity filter undergoes a conformational change reminiscent of that accompanying C-type inactivation of voltage-gated K(+) channels. The noninactivating TRPM2 variant will be invaluable for gating studies. LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Vergani, Paola AU - Gulyas-Kovacs, Attila AU - Gadsby, David C. TI - Electrophysiological, Biochemical, and Bioinformatic Methods for Studying CFTR Channel Gating and Its Regulation JF - METHODS IN MOLECULAR BIOLOGY J2 - METHODS MOL BIOL VL - 741 PY - 2011 SP - 443 EP - 469 PG - 27 SN - 9781617791161 SN - 1064-3745 DO - 10.1007/978-1-61779-117-8_28 UR - https://m2.mtmt.hu/api/publication/32730112 ID - 32730112 N1 - Funding Agency and Grant Number: Medical Research CouncilUK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission [G0501200] Funding Source: Medline; NIDDK NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01 DK051767] Funding Source: Medline; MRCUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [G0501200] Funding Source: UKRI; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK051767] Funding Source: NIH RePORTER AB - CFTR is the only member of the ABC (ATP-binding cassette) protein superfamily known to function as an ion channel. Most other ABC proteins are ATP-driven transporters, in which a cycle of ATP binding and hydrolysis, at intracellular nucleotide binding domains (NBDs), powers uphill substrate translocation across the membrane. In CFTR, this same ATP-driven cycle opens and closes a transmembrane pore through which chloride ions flow rapidly down their electrochemical gradient. Detailed analysis of the pattern of gating of CFTR channels thus offers the opportunity to learn about mechanisms of function not only of CFTR channels but also of their ABC transporter ancestors. In addition, CFTR channel gating is subject to complex regulation by kinase-mediated phosphorylation at multiple consensus sites in a cytoplasmic regulatory domain that is unique to CFTR. Here we offer a practical guide to extract useful information about the mechanisms that control opening and closing of CFTR channels: on how to plan (including information obtained from analysis of multiple sequence alignments), carry out, and analyze electrophysiological and biochemical experiments, as well as on how to circumvent potential pitfalls. LA - English DB - MTMT ER - TY - JOUR AU - Homolya, László AU - Orbán, Tamás I. AU - Csanády, László AU - Sarkadi, Balázs TI - Mitoxantrone is expelled by the ABCG2 multidrug transporter directly from the plasma membrane JF - BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES J2 - BBA-BIOMEMBRANES VL - 1808 PY - 2011 IS - 1 SP - 154 EP - 163 PG - 10 SN - 0005-2736 DO - 10.1016/j.bbamem.2010.07.031 UR - https://m2.mtmt.hu/api/publication/1690127 ID - 1690127 AB - ABC multidrug transporter proteins expel a wide variety of structurally unrelated, mostly hydrophobic compounds from cells. The special role of these transporters both at the physiological barriers and in cancer cells is based on their extremely broad substrate recognition. Since hydrophobic compounds are known to partition into the lipid bilayer and accumulate in membranes. the "classical pump" model for the mechanism of multidrug transporter proteins has been challenged, and alternative models suggesting substrate recognition within the lipid bilayer have been proposed. Although much effort has been made to validate this concept, unambiguous evidence for direct drug extrusion from the plasma membrane has not been provided yet. Here we show a detailed on-line microscopic analysis of cellular extrusion of fluorescent anti-cancer drugs, mitoxantrone and pheophorbide A, by a key human multidrug transporter, ABCG2. Using the fully active GFP-tagged ABCG2 and exploiting the special character of mitoxantrone that gains fluorescence in the lipid environment, we were able to determine transporter-modulated drug concentrations separately in the plasma membrane and the intracellular compartments. Different kinetic models describing the various transport mechanisms were generated and the experimental data were analyzed using these models. On the basis of the kinetic analysis, drug extrusion from the cytoplasm can be excluded, thus, our results indicate that ABCG2 extrudes mitoxantrone directly from the plasma membrane. (C) 2010 Elsevier B.V. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Szöllősi, András AU - Muallem, DR AU - Csanády, László AU - Vergani, P TI - Mutant cycles at CFTR's non-canonical ATP-binding site support little interface separation during gating JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 137 PY - 2011 IS - 6 SP - 549 EP - 562 PG - 14 SN - 0022-1295 DO - 10.1085/jgp.201110608 UR - https://m2.mtmt.hu/api/publication/1690126 ID - 1690126 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Vergani, P AU - Gadsby, DC TI - Strict coupling between CFTR's catalytic cycle and gating of its Cl- ion pore revealed by distributions of open channel burst durations JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 107 PY - 2010 IS - 3 SP - 1241 EP - 1246 PG - 6 SN - 0027-8424 DO - 10.1073/pnas.0911061107 UR - https://m2.mtmt.hu/api/publication/1493081 ID - 1493081 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László TI - Degenerate ABC composite site is stably glued together by trapped ATP JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 135 PY - 2010 IS - 5 SP - 395 EP - 398 PG - 4 SN - 0022-1295 DO - 10.1085/jgp.201010443 UR - https://m2.mtmt.hu/api/publication/1493080 ID - 1493080 N1 - Comment on: Stable ATP binding mediated by a partial NBD dimer of the CFTR chloride channel. [J Gen Physiol. 2010] LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László TI - Permeating proton found guilty in compromising TRPM2 channel activity JF - JOURNAL OF PHYSIOLOGY-LONDON J2 - J PHYSIOL-LONDON VL - 588 PY - 2010 IS - 10 SP - 1661 EP - 1662 PG - 2 SN - 0022-3751 DO - 10.1113/jphysiol.2010.190223 UR - https://m2.mtmt.hu/api/publication/1493079 ID - 1493079 LA - English DB - MTMT ER - TY - JOUR AU - Szöllősi, András AU - Vergani, P AU - Csanády, László TI - Involvement of F1296 and N1303 of CFTR in induced-fit conformational change in response to ATP binding at NBD2 JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 136 PY - 2010 IS - 4 SP - 407 EP - 423 PG - 17 SN - 0022-1295 DO - 10.1085/jgp.201010434 UR - https://m2.mtmt.hu/api/publication/1493077 ID - 1493077 N1 - Department of Medical Biochemistry, Semmelweis University, Budapest H-1094, Hungary Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 7HY, United Kingdom Cited By :17 Export Date: 9 March 2022 CODEN: JGPLA Correspondence Address: Csanády, L.; Department of Medical Biochemistry, , Budapest H-1094, Hungary; email: laszlo.csanady@eok.sote.hu Chemicals/CAS: adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; Adenosine Triphosphate, 56-65-5; Cystic Fibrosis Transmembrane Conductance Regulator, 126880-72-6 Funding details: Medical Research Council, MRC, G0501200 LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Balázs AU - Csanády, László TI - Identification of Direct and Indirect Effectors of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel JF - JOURNAL OF BIOLOGICAL CHEMISTRY J2 - J BIOL CHEM VL - 285 PY - 2010 IS - 39 SP - 30091 EP - 30102 PG - 12 SN - 0021-9258 DO - 10.1074/jbc.M109.066464 UR - https://m2.mtmt.hu/api/publication/1493078 ID - 1493078 LA - English DB - MTMT ER - TY - JOUR AU - Chinopoulos, Christos AU - Sisa-Vajda, Szilvia AU - Csanády, László AU - Mándi, Miklós AU - Mathe, K AU - Ádám, Veronika TI - A novel kinetic assay of mitochondrial ATP-ADP exchange rate mediated by the ANT JF - BIOPHYSICAL JOURNAL J2 - BIOPHYS J VL - 96 PY - 2009 IS - 6 SP - 2490 EP - 2504 PG - 15 SN - 0006-3495 DO - 10.1016/j.bpj.2008.12.3915 UR - https://m2.mtmt.hu/api/publication/1234613 ID - 1234613 N1 - Megjegyzés-22182824 DI: 10.1016/j.bpj.2008.12.3915 AB - A novel method exploiting the differential affinity of ADP and ATP to Mg(2+) was developed to measure mitochondrial ADP-ATP exchange rate. The rate of ATP appearing in the medium after addition of ADP to energized mitochondria, is calculated from the measured rate of change in free extramitochondrial [Mg(2+)] reported by the membrane-impermeable 5K(+) salt of the Mg(2+)-sensitive fluorescent indicator, Magnesium Green, using standard binding equations. The assay is designed such that the adenine nucleotide translocase (ANT) is the sole mediator of changes in [Mg(2+)] in the extramitochondrial volume, as a result of ADP-ATP exchange. We also provide data on the dependence of ATP efflux rate within the 6.8-7.8 matrix pH range as a function of membrane potential. Finally, by comparing the ATP-ADP steady-state exchange rate to the amount of the ANT in rat brain synaptic, brain nonsynaptic, heart and liver mitochondria, we provide molecular turnover numbers for the known ANT isotypes. LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Törőcsik, Beáta TI - Four Ca2+ Ions Activate TRPM2 Channels by Binding in Deep Crevices near the Pore but Intracellularly of the Gate JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 133 PY - 2009 IS - 2 SP - 189 EP - 203 PG - 15 SN - 0022-1295 DO - 10.1085/jgp.200810109 UR - https://m2.mtmt.hu/api/publication/1502468 ID - 1502468 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László TI - Application of rate-equilibrium free energy relationship analysis to nonequilibrium ion channel gating mechanisms JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 134 PY - 2009 IS - 2 SP - 129 EP - 136 PG - 8 SN - 0022-1295 DO - 10.1085/jgp.200910268 UR - https://m2.mtmt.hu/api/publication/1493082 ID - 1493082 N1 - Cited By :8 Export Date: 9 March 2022 CODEN: JGPLA Correspondence Address: Csanády, L.; Department of Medical Biochemistry, , Budapest H-1094, Hungary; email: laszlo.csanady@-eok.sote.hu Chemicals/CAS: adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; Ion Channels Funding details: Fogarty International Center, FIC, R03TW007829 Funding details: National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK, R01DK051767 LA - English DB - MTMT ER - TY - JOUR AU - Chan, KW AU - Wheeler, A AU - Csanády, László TI - Sulfonylurea receptors type 1 and 2A randomly assemble to form heteromeric K-ATP channels of mixed subunit composition JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 131 PY - 2008 IS - 1 SP - 43 EP - 58 PG - 16 SN - 0022-1295 DO - 10.1085/jgp.200709894 UR - https://m2.mtmt.hu/api/publication/1493084 ID - 1493084 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Mindell, JA TI - The twain shall meet: channels, transporters and things between - Meeting on Membrane Transport in Flux: The Ambiguous Interface between Channels and Pumps JF - EMBO REPORTS J2 - EMBO REP VL - 9 PY - 2008 IS - 10 SP - 960 EP - 965 PG - 6 SN - 1469-221X DO - 10.1038/embor.2008.172 UR - https://m2.mtmt.hu/api/publication/1493083 ID - 1493083 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László TI - Statistical evaluation of ion-channel gating models based on distributions of log-likelihood ratios JF - BIOPHYSICAL JOURNAL J2 - BIOPHYS J VL - 90 PY - 2006 IS - 10 SP - 3523 EP - 3545 PG - 23 SN - 0006-3495 DO - 10.1529/biophysj.105.075135 UR - https://m2.mtmt.hu/api/publication/1493087 ID - 1493087 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Nairn, AC AU - Gadsby, DC TI - Thermodynamics of CFTR channel gating: A spreading conformational change initiates an irreversible gating cycle JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 128 PY - 2006 IS - 5 SP - 523 EP - 533 PG - 11 SN - 0022-1295 DO - 10.1085/jgp.200609558 UR - https://m2.mtmt.hu/api/publication/1493085 ID - 1493085 N1 - Cited By :45 Export Date: 9 March 2022 CODEN: JGPLA Correspondence Address: Csanády, L.; Department of Medical Biochemistry, , 1088 Budapest, Hungary; email: csanady@puskin.sote.hu Chemicals/CAS: adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; adenylylimidodiphosphate, 25612-73-1; Adenosine Triphosphate, 56-65-5; ATP-Binding Cassette Transporters; Cyclic AMP-Dependent Protein Kinases, EC 2.7.1.37; Cystic Fibrosis Transmembrane Conductance Regulator, 126880-72-6 Funding details: Fogarty International Center, FIC, R03TW005761 Funding details: National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK, R01DK051767 LA - English DB - MTMT ER - TY - JOUR AU - Fang, K AU - Csanády, László AU - Chan, KW TI - The N-terminal transmembrane domain (TMD0) and a cytosolic linker (L0) of sulphonylurea receptor define the unique intrinsic gating of K-ATP channels JF - JOURNAL OF PHYSIOLOGY-LONDON J2 - J PHYSIOL-LONDON VL - 576 PY - 2006 IS - 2 SP - 379 EP - 389 PG - 11 SN - 0022-3751 DO - 10.1113/jphysiol.2006.112748 UR - https://m2.mtmt.hu/api/publication/1493086 ID - 1493086 LA - English DB - MTMT ER - TY - JOUR AU - Gadsby, DC AU - Vergani, P AU - Csanády, László TI - The ABC protein turned chloride channel whose failure causes cystic fibrosis JF - NATURE J2 - NATURE VL - 440 PY - 2006 IS - 7083 SP - 477 EP - 483 PG - 7 SN - 0028-0836 DO - 10.1038/nature04712 UR - https://m2.mtmt.hu/api/publication/1493088 ID - 1493088 N1 - Funding Agency and Grant Number: Medical Research CouncilUK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission [G0501200] Funding Source: Medline; NIDDK NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01 DK051767, R01 DK051767-10] Funding Source: Medline; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK051767] Funding Source: NIH RePORTER Cited By :498 Export Date: 31 August 2021 CODEN: NATUA Correspondence Address: Gadsby, D.C.; Laboratory of Cardiac/Membrane Physiology, Rockefeller University, New York, NY 10021, United States; email: gadsby@rockefeller.edu LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Chan, KW AU - Nairn, AC AU - Gadsby, DC TI - Functional roles of nonconserved structural segments in CFTR's NH2-terminal nucleotide binding domain JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 125 PY - 2005 IS - 1 SP - 43 EP - 55 PG - 13 SN - 0022-1295 DO - 10.1085/jgp.200409174 UR - https://m2.mtmt.hu/api/publication/1493090 ID - 1493090 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Seto-Young, D AU - Chan, KW AU - Cenciarelli, C AU - Angel, BB AU - Qin, J AU - McLachlin, DT AU - Krutchinsky, AN AU - Chait, BT AU - Nairn, AC AU - Gadsby, DC TI - Preferential phosphorylation of R-domain serine 768 dampens activation of CFTR channels by PKA JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 125 PY - 2005 IS - 2 SP - 171 EP - 186 PG - 16 SN - 0022-1295 DO - 10.1085/jgp.200409076 UR - https://m2.mtmt.hu/api/publication/1493089 ID - 1493089 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Ádám, Veronika TI - Antagonistic regulation of native Ca2+- and ATP-sensitive cation channels in brain capillaries by nucleotides and decavanadate JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 123 PY - 2004 IS - 6 SP - 743 EP - 757 PG - 15 SN - 0022-1295 DO - 10.1085/jgp.200309008 UR - https://m2.mtmt.hu/api/publication/1030898 ID - 1030898 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Ádám, Veronika TI - Ca2+- and voltage-dependent gating of Ca2+- and ATP-sensitive cationic channels in brain capillary endothelium JF - BIOPHYSICAL JOURNAL J2 - BIOPHYS J VL - 85 PY - 2003 IS - 1 SP - 313 EP - 327 PG - 15 SN - 0006-3495 DO - 10.1016/S0006-3495(03)74476-2 UR - https://m2.mtmt.hu/api/publication/1030904 ID - 1030904 LA - English DB - MTMT ER - TY - JOUR AU - Chan, KW AU - Csanády, László AU - Seto-Young, D AU - Nairn, AC AU - Gadsby, DC TI - Severed molecules functionally define the boundaries of the cystic fibrosis transmembrane conductance regulator's NH2-terminal nucleotide binding domain JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 116 PY - 2000 IS - 2 SP - 163 EP - 180 PG - 18 SN - 0022-1295 DO - 10.1085/jgp.116.2.163 UR - https://m2.mtmt.hu/api/publication/1493091 ID - 1493091 N1 - Összes idézések száma a WoS-ban: 0 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Chan, KW AU - Seto-Young, D AU - Kopsco, DC AU - Nairn, AC AU - Gadsby, DC TI - Severed channels probe regulation of gating of cystic fibrosis transmembrane conductance regulator by its cytoplasmic domains JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 116 PY - 2000 IS - 3 SP - 477 EP - 500 PG - 24 SN - 0022-1295 DO - 10.1085/jgp.116.3.477 UR - https://m2.mtmt.hu/api/publication/1493767 ID - 1493767 N1 - Laboratory of Cardiac/Membrane Physiology, Rockefeller University, New York, NY 10021-6399, United States Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10021-6399, United States Laboratory of Cardiac/Membrane Physiology, Rockefeller University, 1230 York Avenue, New York, NY 10021-6399, United States Cited By :99 Export Date: 27 February 2023 CODEN: JGPLA Correspondence Address: Gadsby, D.C.; Lab. of Cardiac/Membrane Physiology, 1230 York Avenue, New York, NY 10021-6399, United States; email: gadsby@rockvax.rockefeller.edu Chemicals/CAS: Adenosine Triphosphate, 56-65-5; Adenylyl Imidodiphosphate, 25612-73-1; CFTR protein, human; Cyclic AMP-Dependent Protein Kinases, EC 2.7.1.37; Cystic Fibrosis Transmembrane Conductance Regulator, 126880-72-6; DNA Primers; Recombinant Proteins Funding details: National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK, R01DK051767 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László TI - Rapid kinetic analysis of multichannel records by a simultaneous fit to all dwell-time histograms JF - BIOPHYSICAL JOURNAL J2 - BIOPHYS J VL - 78 PY - 2000 IS - 2 SP - 785 EP - 799 PG - 15 SN - 0006-3495 DO - 10.1016/S0006-3495(00)76636-7 UR - https://m2.mtmt.hu/api/publication/1493092 ID - 1493092 LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Gadsby, DC TI - CFTR channel gating: Incremental progress in irreversible steps JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 114 PY - 1999 IS - 1 SP - 49 EP - 53 PG - 5 SN - 0022-1295 DO - 10.1085/jgp.114.1.49 UR - https://m2.mtmt.hu/api/publication/1493093 ID - 1493093 N1 - Comment on: Dual effects of ADP and adenylylimidodiphosphate on CFTR channel kinetics show binding to two different nucleotide binding sites. [J Gen Physiol. 1999] LA - English DB - MTMT ER -