TY - JOUR AU - Bobkov, D. AU - Semenova, S. TI - Impact of lipid rafts on transient receptor potential channel activities JF - JOURNAL OF CELLULAR PHYSIOLOGY J2 - J CELL PHYSIOL VL - 237 PY - 2022 IS - 4 SP - 2034 EP - 2044 PG - 11 SN - 0021-9541 DO - 10.1002/jcp.30679 UR - https://m2.mtmt.hu/api/publication/32597571 ID - 32597571 N1 - Export Date: 17 January 2022 CODEN: JCLLA Correspondence Address: Semenova, S.; Laboratory of Ionic Mechanisms of Cell Signaling, Russian Federation; email: svsem@incras.ru LA - English DB - MTMT ER - TY - JOUR AU - Gutorov, Rita AU - Katz, Ben AU - Rhodes-Mordov, Elisheva AU - Zaguri, Rachel AU - Brandwine-Shemmer, Tal AU - Minke, Baruch TI - The Role of Membrane Lipids in Light-Activation of Drosophila TRP Channels JF - BIOMOLECULES J2 - BIOMOLECULES VL - 12 PY - 2022 IS - 3 PG - 19 SN - 2218-273X DO - 10.3390/biom12030382 UR - https://m2.mtmt.hu/api/publication/33344914 ID - 33344914 AB - Transient Receptor Potential (TRP) channels constitute a large superfamily of polymodal channel proteins with diverse roles in many physiological and sensory systems that function both as ionotropic and metabotropic receptors. From the early days of TRP channel discovery, membrane lipids were suggested to play a fundamental role in channel activation and regulation. A prominent example is the Drosophila TRP and TRP-like (TRPL) channels, which are predominantly expressed in the visual system of Drosophila. Light activation of the TRP and TRPL channels, the founding members of the TRP channel superfamily, requires activation of phospholipase C beta (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into Diacylglycerol (DAG) and Inositol 1,4,5-trisphosphate (IP3). However, the events required for channel gating downstream of PLC activation are still under debate and led to several hypotheses regarding the mechanisms by which lipids gate the channels. Despite many efforts, compelling evidence of the involvement of DAG accumulation, PIP2 depletion or IP3-mediated Ca2+ release in light activation of the TRP/TRPL channels are still lacking. Exogeneous application of poly unsaturated fatty acids (PUFAs), a product of DAG hydrolysis was demonstrated as an efficient way to activate the Drosophila TRP/TRPL channels. However, compelling evidence for the involvement of PUFAs in physiological light-activation of the TRP/TRPL channels is still lacking. Light-induced mechanical force generation was measured in photoreceptor cells prior to channel opening. This mechanical force depends on PLC activity, suggesting that the enzymatic activity of PLC converting PIP2 into DAG generates membrane tension, leading to mechanical gating of the channels. In this review, we will present the roles of membrane lipids in light activation of Drosophila TRP channels and present the many advantages of this model system in the exploration of TRP channel activation under physiological conditions. LA - English DB - MTMT ER - TY - JOUR AU - Wan, Kirsty Y. AU - Jékely, Gáspár TI - Origins of eukaryotic excitability JF - PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B - BIOLOGICAL SCIENCES J2 - PHILOS T ROY SOC B VL - 376 PY - 2021 IS - 1820 SN - 0962-8436 DO - 10.1098/rstb.2019.0758 UR - https://m2.mtmt.hu/api/publication/31851708 ID - 31851708 N1 - Funding Agency and Grant Number: European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programmeEuropean Research Council (ERC) [853560]; Leverhulme TrustLeverhulme Trust [RPG-2018-392] Funding text: K.Y.W. gratefully acknowledges funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under grant agreement no. 853560: 'EvoMotion'-Moving around without a brain: Evolution of basal cognition in single-celled organisms. G.J. would like to thank the Leverhulme Trust for funding (RPG-2018-392). LA - English DB - MTMT ER - TY - JOUR AU - Montesinos, Jorge AU - Guardia-Laguarta, Cristina AU - Area-Gomez, Estela TI - The fat brain JF - CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE J2 - CURR OPIN CLIN NUTR VL - 23 PY - 2020 IS - 2 SP - 68 EP - 75 PG - 8 SN - 1363-1950 DO - 10.1097/MCO.0000000000000634 UR - https://m2.mtmt.hu/api/publication/31505504 ID - 31505504 AB - Purpose of review The purpose of this brief review is to gain an understanding on the multiple roles that lipids exert on the brain, and to highlight new ideas in the impact of lipid homeostasis in the regulation of synaptic transmission. Recent findings Recent data underline the crucial function of lipid homeostasis in maintaining neuronal function and synaptic plasticity. Moreover, new advances in analytical approaches to study lipid classes and species is opening a new door to understand and monitor how alterations in lipid pathways could shed new light into the pathogenesis of neurodegeneration. Lipids are one of the most essential elements of the brain. However, our understanding of the role of lipids within the central nervous system is still largely unknown. Identifying the molecular mechanism (s) by which lipids can regulate neuronal transmission represents the next frontier in neuroscience, and a new challenge in our understanding of the brain and the mechanism(s) behind neurological disorders. LA - English DB - MTMT ER - TY - JOUR AU - Zákány, Florina AU - Kovács, Tamás AU - Panyi, György AU - Varga, Zoltán TI - Direct and indirect cholesterol effects on membrane proteins with special focus on potassium channels JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS J2 - BBA-MOL CELL BIOL L VL - 1865 PY - 2020 IS - 8 SN - 1388-1981 DO - 10.1016/j.bbalip.2020.158706 UR - https://m2.mtmt.hu/api/publication/31312818 ID - 31312818 N1 - Division of Biophysics, Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, Debrecen, H-4032, Hungary Doctoral School of Molecular Medicine, University of Debrecen, Egyetem ter 1, Debrecen, H-4032, Hungary Export Date: 14 May 2020 CODEN: BBMLF Correspondence Address: Varga, Z.; Division of Biophysics, Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, Hungary; email: veze@med.unideb.hu Chemicals/CAS: adenosine triphosphatase (potassium sodium); calcium, 7440-70-2, 14092-94-5; cholesterol, 57-88-5; epidermal growth factor receptor, 79079-06-4; potassium, 7440-09-7; protein tyrosine kinase, 80449-02-1; sodium, 7440-23-5 Funding details: Emberi Eroforrások Minisztériuma, EMMI, ÚNKP-19-3-III-DE-92 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFI, K120302, GINOP-2.3.2-15-2016-00015, EFOP-3.6.2-16-2017-00006, K119417, GINOP-2.3.2-15-2016-00020 Funding details: Magyar Tudományos Akadémia, MTA, KTIA_NAP_13-2-2015-0009, KTIA_NAP_13-2-2017-0013 Funding details: Hungarian Scientific Research Fund, OTKA, K132906, ÚNKP-18-3-IV-DE-54 Funding text 1: This work was supported by the Hungarian Academy of Sciences projects KTIA_NAP_13-2-2015-0009 and KTIA_NAP_13-2-2017-0013 (Z.V.); OTKA K132906 (Z.V.), the ÚNKP-18-3-IV-DE-54 New National Excellence Program of the Ministry of Human Capacities (F.Z.); ÚNKP-19-3-III-DE-92 New National Excellence Program of the Ministry for Innovation and Technology (F.Z.), the National Research Development and Innovation Office ( GINOP-2.3.2-15-2016-00020 ) (T.K.), EFOP-3.6.2-16-2017-00006 (G.P.), GINOP-2.3.2-15-2016-00015 (G.P.) and OTKA K119417 (G.P., F.Z.) and K120302 (T.K.). Division of Biophysics, Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, Debrecen, H-4032, Hungary Doctoral School of Molecular Medicine, University of Debrecen, Egyetem ter 1, Debrecen, H-4032, Hungary Export Date: 15 May 2020 CODEN: BBMLF Correspondence Address: Varga, Z.; Division of Biophysics, Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, Hungary; email: veze@med.unideb.hu Chemicals/CAS: adenosine triphosphatase (potassium sodium); calcium, 7440-70-2, 14092-94-5; cholesterol, 57-88-5; epidermal growth factor receptor, 79079-06-4; potassium, 7440-09-7; protein tyrosine kinase, 80449-02-1; sodium, 7440-23-5 Funding details: Emberi Eroforrások Minisztériuma, EMMI, ÚNKP-19-3-III-DE-92 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFI, K120302, GINOP-2.3.2-15-2016-00015, EFOP-3.6.2-16-2017-00006, K119417, GINOP-2.3.2-15-2016-00020 Funding details: Magyar Tudományos Akadémia, MTA, KTIA_NAP_13-2-2015-0009, KTIA_NAP_13-2-2017-0013 Funding details: Hungarian Scientific Research Fund, OTKA, K132906, ÚNKP-18-3-IV-DE-54 Funding text 1: This work was supported by the Hungarian Academy of Sciences projects KTIA_NAP_13-2-2015-0009 and KTIA_NAP_13-2-2017-0013 (Z.V.); OTKA K132906 (Z.V.), the ÚNKP-18-3-IV-DE-54 New National Excellence Program of the Ministry of Human Capacities (F.Z.); ÚNKP-19-3-III-DE-92 New National Excellence Program of the Ministry for Innovation and Technology (F.Z.), the National Research Development and Innovation Office ( GINOP-2.3.2-15-2016-00020 ) (T.K.), EFOP-3.6.2-16-2017-00006 (G.P.), GINOP-2.3.2-15-2016-00015 (G.P.) and OTKA K119417 (G.P., F.Z.) and K120302 (T.K.). AB - As described in the literature the interaction between cholesterol and membrane proteins can occur via direct, ligand-like and indirect mechanisms, in which cholesterol effects are mediated by alterations in the biophysical properties or in the protein-organizing functions of the lipid membrane. Early studies emphasized the importance of indirect and raft-mediated effects, but improvements in computational and structural imaging techniques allowed the definition of a wide range of functionally active cholesterol binding domains and sites suggesting the relevance of direct cholesterol effects in various proteins. However, the intramolecular rearrangements induced by cholesterol leading to modulation of ion channel gating, membrane transport and receptor functions still have not been revealed. In this review we summarize the novel findings of the topic by focusing on recent studies about direct and indirect effects of cholesterol on potassium ion channels, and we extend the review to transporters and receptors with different domain structures to introduce the general mechanisms of cholesterol action among membrane proteins. We propose that rather than pure direct or indirect effects, cholesterol action on membrane proteins can be better described as a mixture of indirect and direct interactions with system-specific variability in their contributions, which can be explored by using a multi-level approach employing multiple experimental techniques. © 2020 The Authors LA - English DB - MTMT ER - TY - JOUR AU - Acharya, Aviseka AU - Brungs, Sonja AU - Lichterfeld, Yannick AU - Hescheler, Jürgen AU - Hemmersbach, Ruth AU - Boeuf, Helene AU - Sachinidis, Agapios TI - Parabolic, Flight-Induced, Acute Hypergravity and Microgravity Effects on the Beating Rate of Human Cardiomyocytes JF - CELLS J2 - CELLS-BASEL VL - 8 PY - 2019 IS - 4 SN - 2073-4409 DO - 10.3390/cells8040352 UR - https://m2.mtmt.hu/api/publication/30663422 ID - 30663422 LA - English DB - MTMT ER - TY - CHAP AU - Barbera, Nicolas AU - Levitan, Irena ED - RosenhouseDantsker, A ED - Bukiya, AN TI - Chiral Specificity of Cholesterol Orientation Within Cholesterol Binding Sites in Inwardly Rectifying K+ Channels T2 - Direct Mechanisms in Cholesterol Modulation of Protein Function PB - [s.n.] CY - Cham SN - 9783030142650 ; 9783030142643 T3 - Advances in Experimental Medicine and Biology, ISSN 0065-2598 ; 1135. PY - 2019 SP - 77 EP - 95 PG - 19 DO - 10.1007/978-3-030-04278-3_4 UR - https://m2.mtmt.hu/api/publication/31069060 ID - 31069060 AB - Cholesterol is an integral component of cellular membranes and has been shown to be an important functional regulator for many different ion channels, including inwardly rectifying potassium (Kir) channels. Consequently, understanding the molecular mechanisms underlying this regulation represents a critical field of study. Broadly speaking, cholesterol can mediate ion channel function either directly by binding to specific sites or indirectly by altering surrounding membrane properties. Owing to the similar effects of cholesterol and its chiral isomers (epicholesterol and ent-cholesterol) on membrane properties, comparative analysis of these sterols can be an effective tool for discriminating between these direct and indirect effects. Indeed, this strategy was used to demonstrate the direct effect of cholesterol on Kir channel function. However, while this approach can discriminate between direct and indirect effects, it does not account for the promiscuity of cholesterol binding sites, which can potentially accommodate cholesterol or its chiral isomers. In this chapter, we use docking analyses to explore the idea that the specificity of cholesterol's effect on Kir channels is dependent on the specific orientation of cholesterol within its putative binding pocket which its chiral isomers cannot replicate, even when bound themselves. LA - English DB - MTMT ER - TY - JOUR AU - Gutorov, R. AU - Peters, M. AU - Katz, B. AU - Brandwine, T. AU - Barbera, N.A. AU - Levitan, I. AU - Minke, B. TI - Modulation of transient receptor potential c channel activity by cholesterol JF - FRONTIERS IN PHARMACOLOGY J2 - FRONT PHARMACOL VL - 10 PY - 2019 SN - 1663-9812 DO - 10.3389/fphar.2019.01487 UR - https://m2.mtmt.hu/api/publication/31041858 ID - 31041858 N1 - Institute for Medical Research Israel-Canada (IMRIC), Edmond and Lily Safra Center for Brain Sciences (ELSC), Faculty of Medicine, Hebrew University, Jerusalem, Israel Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States Export Date: 7 January 2020 Correspondence Address: Minke, B.; Institute for Medical Research Israel-Canada (IMRIC), Edmond and Lily Safra Center for Brain Sciences (ELSC), Faculty of Medicine, Hebrew UniversityIsrael; email: baruchm@ekmd.huji.ac.il Funding details: United States-Israel Binational Science Foundation, BSF Funding details: Grant Foundation, 2015014 Funding text 1: This study was supported by the United States-Israel Binational Science Foundation grant no. 2015014 (BM and IL). AB - Changes of cholesterol level in the plasma membrane of cells have been shown to modulate ion channel function. The proposed mechanisms underlying these modulations include association of cholesterol to a single binding site at a single channel conformation, association to a highly flexible cholesterol binding site adopting multiple poses, and perturbation of lipid rafts. These perturbations have been shown to induce reversible targeting of mammalian transient receptor potential C (TRPC) channels to the cholesterol-rich membrane environment of lipid rafts. Thus, the observed inhibition of TRPC channels by methyl-β-cyclodextrin (MβCD), which induces cholesterol efflux from the plasma membrane, may result from disruption of lipid rafts. This perturbation was also shown to disrupt multimolecular signaling complexes containing TRPC channels. The Drosophila TRP and TRP-like (TRPL) channels belong to the TRPC channel subfamily. When the Drosophila TRPL channel was expressed in S2 or HEK293 cells and perfused with MβCD, the TRPL current was abolished in less than 100 s, fitting well the fast kinetic phase of cholesterol sequestration experiments in cells. It was thus suggested that the fast kinetics of TRPL channel suppression by MβCD arise from disruption of lipid rafts. Accordingly, lipid raft perturbation by cholesterol sequestration could give clues to the function of lipid environment in TRPC channel activity and its mechanism. Copyright © 2019 Gutorov, Peters, Katz, Brandwine, Barbera, Levitan and Minke. LA - English DB - MTMT ER - TY - CHAP AU - Rosenhouse-Dantsker, Avia ED - RosenhouseDantsker, A ED - Bukiya, AN TI - Cholesterol Binding Sites in Inwardly Rectifying Potassium Channels T2 - Direct Mechanisms in Cholesterol Modulation of Protein Function PB - [s.n.] CY - Cham SN - 9783030142650 ; 9783030142643 T3 - Advances in Experimental Medicine and Biology, ISSN 0065-2598 ; 1135. PY - 2019 SP - 119 EP - 138 PG - 20 DO - 10.1007/978-3-030-14265-0_7 UR - https://m2.mtmt.hu/api/publication/30766400 ID - 30766400 AB - Inwardly rectifying potassium (Kir) channels play a variety of critical cellular roles including modulating membrane excitability in neurons, cardiomyocytes and muscle cells, and setting the resting membrane potential, heart rate, vascular tone, insulin release, and salt flow across epithelia. These processes are regulated by a variegated list of modulators. In particular, in recent years, cholesterol has been shown to modulate a growing number of Kir channels. Subsequent to the discovery that members of the Kir2 subfamily were down-regulated by cholesterol, we have shown that members of several other Kir subfamilies were also modulated by cholesterol. However, not all cholesterol sensitive Kir channels were down-regulated by cholesterol. Our recent studies focused on three Kir channels: Kir2.1 (IRK1), Kir3.2(boolean AND) (GIRK2(boolean AND)) and Kir3.4* (GIRK4*). Among these, Kir2.1 was down-regulated by cholesterol whereas Kir3.2(boolean AND) and Kir3.4* were both up-regulated by cholesterol. Despite the opposite impact of cholesterol on these Kir3 channels compared to Kir2.1, putative cholesterol binding sites in all three channels were identified in equivalent transmembrane domains. Interestingly, however, there are intriguing differences in the specific residues that interact with the cholesterol molecule in these Kir channels. Here we compare and contrast the molecular characteristics of the putative cholesterol binding sites in the three channels, and discuss the potential implications of the differences for the impact of cholesterol on ion channels. LA - English DB - MTMT ER - TY - JOUR AU - Zákány, Florina AU - Pap, Pál AU - Papp, Ferenc AU - Kovács, Tamás AU - Nagy, Péter AU - Péter, Mária AU - Szente, Lajos AU - Panyi, György AU - Varga, Zoltán TI - Determining the target of membrane sterols on voltage-gated potassium channels JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS J2 - BBA-MOL CELL BIOL L VL - 1864 PY - 2019 IS - 3 SP - 312 EP - 325 PG - 14 SN - 1388-1981 DO - 10.1016/j.bbalip.2018.12.006 UR - https://m2.mtmt.hu/api/publication/30378432 ID - 30378432 N1 - Division of Biophysics, Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, Debrecen, H-4032, Hungary MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, University of Debrecen, Egyetem ter 1, Debrecen, H-4032, Hungary Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Temesvari Krt. 62, Szeged, H-6726, Hungary CycloLab Cyclodextrin R & D Laboratory Ltd., Illatos u. 7, Budapest, H-1097, Hungary Export Date: 7 January 2019 CODEN: BBMLF Correspondence Address: Varga, Z.; Division of Biophysics, Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, Hungary; email: veze@med.unideb.hu Division of Biophysics, Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, Debrecen, H-4032, Hungary MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, University of Debrecen, Egyetem ter 1, Debrecen, H-4032, Hungary Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Temesvari Krt. 62, Szeged, H-6726, Hungary CycloLab Cyclodextrin R & D Laboratory Ltd., Illatos u. 7, Budapest, H-1097, Hungary Cited By :1 Export Date: 27 September 2019 CODEN: BBMLF Correspondence Address: Varga, Z.; Division of Biophysics, Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, Hungary; email: veze@med.unideb.hu LA - English DB - MTMT ER - TY - JOUR AU - Barbera, Nicolas AU - Ayee, Manuela A. A. AU - Akpa, Belinda S. AU - Levitan, Irena TI - Molecular Dynamics Simulations of Kir2.2 Interactions with an Ensemble of Cholesterol Molecules JF - BIOPHYSICAL JOURNAL J2 - BIOPHYS J VL - 115 PY - 2018 IS - 7 SP - 1264 EP - 1280 PG - 17 SN - 0006-3495 DO - 10.1016/j.bpj.2018.07.041 UR - https://m2.mtmt.hu/api/publication/30572352 ID - 30572352 AB - Cholesterol is a major regulator of multiple types of ion channels, but the specific mechanisms and the dynamics of its interactions with the channels are not well understood. Kir2 channels were shown to be sensitive to cholesterol through direct interactions with "cholesterol-sensitive" regions on the channel protein. In this work, we used Martini coarse-grained simulations to analyze the long (us) timescale dynamics of cholesterol with Kir2.2 channels embedded into a model membrane containing POPC phospholipid with 30 mol% cholesterol. This approach allows us to simulate the dynamic, unbiased migration of cholesterol molecules from the lipid membrane environment to the protein surface of Kir2.2 and explore the favorability of cholesterol interactions at both surface sites and recessed pockets of the channel. We found that the cholesterol environment surrounding Kir channels forms a complex milieu of different short- and long-term interactions, with multiple cholesterol molecules concurrently interacting with the channel. Furthermore, utilizing principles from network theory, we identified four discrete cholesterol-binding sites within the previously identified cholesterol-sensitive region that exist depending on the conformational state of the channel-open or closed. We also discovered that a twofold decrease in the cholesterol level of the membrane, which we found earlier to increase Kir2 activity, results in a site-specific decrease of cholesterol occupancy at these sites in both the open and closed states: cholesterol molecules at the deepest of these discrete sites shows no change in occupancy at different cholesterol levels, whereas the remaining sites showed a marked decrease in occupancy. LA - English DB - MTMT ER -