@article{MTMT:31365406,
	title = {Selective profiling of N- And C-terminal nucleotide-binding sites in a TRPM2 channel},
	url = {https://m2.mtmt.hu/api/publication/31365406},
	author = {Tóth, Balázs and Iordanov, Iordan and Csanády, László},
	doi = {10.1085/jgp.201912533},
	journal-iso = {J GEN PHYSIOL},
	journal = {JOURNAL OF GENERAL PHYSIOLOGY},
	volume = {152},
	unique-id = {31365406},
	issn = {0022-1295},
	abstract = {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/).},
	year = {2020},
	eissn = {1540-7748},
	orcid-numbers = {Tóth, Balázs/0000-0002-1257-2597; Iordanov, Iordan/0000-0001-8251-5857; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:30637149,
	title = {Enzyme activity and selectivity filter stability of ancient TRPM2 channels were simultaneously lost in early vertebrates},
	url = {https://m2.mtmt.hu/api/publication/30637149},
	author = {Iordanov, Iordan and Tóth, Balázs and Szöllősi, András and Csanády, László},
	doi = {10.7554/eLife.44556},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {8},
	unique-id = {30637149},
	issn = {2050-084X},
	abstract = {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.},
	keywords = {Xenopus; E. coli; molecular biophysics; Structural biology; Selectivity filter; ADP ribose; Nudix hydrolase; channel enzyme; rundown},
	year = {2019},
	eissn = {2050-084X},
	orcid-numbers = {Iordanov, Iordan/0000-0001-8251-5857; Tóth, Balázs/0000-0002-1257-2597; Szöllősi, András/0000-0002-5570-4609; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:30465914,
	title = {Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation},
	url = {https://m2.mtmt.hu/api/publication/30465914},
	author = {Zhang, Zhe and Tóth, Balázs and Szöllősi, András and Chen, Jue and Csanády, László},
	doi = {10.7554/eLife.36409},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {7},
	unique-id = {30465914},
	issn = {2050-084X},
	abstract = {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.},
	year = {2018},
	eissn = {2050-084X},
	orcid-numbers = {Tóth, Balázs/0000-0002-1257-2597; Szöllősi, András/0000-0002-5570-4609; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:3105008,
	title = {The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity},
	url = {https://m2.mtmt.hu/api/publication/3105008},
	author = {Iordanov, Iordan and Mihályi, Csaba and Tóth, Balázs and Csanády, László},
	doi = {10.7554/eLife.17600},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {5},
	unique-id = {3105008},
	issn = {2050-084X},
	year = {2016},
	eissn = {2050-084X},
	orcid-numbers = {Iordanov, Iordan/0000-0001-8251-5857; Mihályi, Csaba/0000-0001-7536-3066; Tóth, Balázs/0000-0002-1257-2597; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:2949645,
	title = {Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2'-phosphate},
	url = {https://m2.mtmt.hu/api/publication/2949645},
	author = {Tóth, Balázs and Iordanov, Iordan and Csanády, László},
	doi = {10.1085/jgp.201511377},
	journal-iso = {J GEN PHYSIOL},
	journal = {JOURNAL OF GENERAL PHYSIOLOGY},
	volume = {145},
	unique-id = {2949645},
	issn = {0022-1295},
	abstract = {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.},
	year = {2015},
	eissn = {1540-7748},
	pages = {419-430},
	orcid-numbers = {Tóth, Balázs/0000-0002-1257-2597; Iordanov, Iordan/0000-0001-8251-5857; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:2762109,
	title = {Putative chanzyme activity of TRPM2 cation channel is unrelated to pore gating},
	url = {https://m2.mtmt.hu/api/publication/2762109},
	author = {Tóth, Balázs and Iordanov, Iordan and Csanády, László},
	doi = {10.1073/pnas.1412449111},
	journal-iso = {P NATL ACAD SCI USA},
	journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
	volume = {111},
	unique-id = {2762109},
	issn = {0027-8424},
	year = {2014},
	eissn = {1091-6490},
	pages = {16949-16954},
	orcid-numbers = {Tóth, Balázs/0000-0002-1257-2597; Iordanov, Iordan/0000-0001-8251-5857; Csanády, László/0000-0002-6547-5889}
}

@mastersthesis{MTMT:2787028,
	title = {A TRPM2 csatorna szerkezet-funkció vizsgálata},
	url = {https://m2.mtmt.hu/api/publication/2787028},
	author = {Tóth, Balázs},
	doi = {10.14753/SE.2013.1814},
	unique-id = {2787028},
	year = {2013},
	orcid-numbers = {Tóth, Balázs/0000-0002-1257-2597}
}

@article{MTMT:2041974,
	title = {Pore collapse underlies irreversible inactivation of TRPM2 cation channel currents.},
	url = {https://m2.mtmt.hu/api/publication/2041974},
	author = {Tóth, Balázs and Csanády, László},
	doi = {10.1073/pnas.1204702109},
	journal-iso = {P NATL ACAD SCI USA},
	journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
	volume = {109},
	unique-id = {2041974},
	issn = {0027-8424},
	abstract = {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.},
	year = {2012},
	eissn = {1091-6490},
	pages = {13440-13445},
	orcid-numbers = {Tóth, Balázs/0000-0002-1257-2597; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:1493078,
	title = {Identification of Direct and Indirect Effectors of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel},
	url = {https://m2.mtmt.hu/api/publication/1493078},
	author = {Tóth, Balázs and Csanády, László},
	doi = {10.1074/jbc.M109.066464},
	journal-iso = {J BIOL CHEM},
	journal = {JOURNAL OF BIOLOGICAL CHEMISTRY},
	volume = {285},
	unique-id = {1493078},
	issn = {0021-9258},
	year = {2010},
	eissn = {1083-351X},
	pages = {30091-30102},
	orcid-numbers = {Tóth, Balázs/0000-0002-1257-2597; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:1499249,
	title = {Ca-2+ release triggered by NAADP in hepatocytes},
	url = {https://m2.mtmt.hu/api/publication/1499249},
	author = {Mándi, Miklós and Tóth, Balázs and Bak, Judit},
	journal-iso = {ACTA PHYSIOL HUNG},
	journal = {ACTA PHYSIOLOGICA HUNGARICA},
	volume = {94},
	unique-id = {1499249},
	issn = {0231-424X},
	year = {2007},
	eissn = {1588-2683},
	pages = {371-372},
	orcid-numbers = {Tóth, Balázs/0000-0002-1257-2597; Bak, Judit/0000-0003-4024-6286}
}