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Proc Natl Acad Sci U S A
2012 Aug 14;10933:13440-5. doi: 10.1073/pnas.1204702109.
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Pore collapse underlies irreversible inactivation of TRPM2 cation channel currents.
Tóth B
,
Csanády L
.
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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.
Baukrowitz,
Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms.
1995, Pubmed
Baukrowitz,
Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms.
1995,
Pubmed
Brelidze,
A ring of eight conserved negatively charged amino acids doubles the conductance of BK channels and prevents inward rectification.
2003,
Pubmed
,
Xenbase
Csanády,
Four Ca2+ ions activate TRPM2 channels by binding in deep crevices near the pore but intracellularly of the gate.
2009,
Pubmed
,
Xenbase
Cuello,
Structural mechanism of C-type inactivation in K(+) channels.
2010,
Pubmed
Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed
Du,
Modulation of TRPM2 by acidic pH and the underlying mechanisms for pH sensitivity.
2009,
Pubmed
Hansen,
Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.
2011,
Pubmed
Hara,
LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death.
2002,
Pubmed
Huang,
Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma.
1998,
Pubmed
,
Xenbase
Imoto,
Rings of negatively charged amino acids determine the acetylcholine receptor channel conductance.
1988,
Pubmed
,
Xenbase
Lange,
TRPM2 functions as a lysosomal Ca2+-release channel in beta cells.
2009,
Pubmed
Liu,
Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5.
2003,
Pubmed
Nilius,
The selectivity filter of the cation channel TRPM4.
2005,
Pubmed
Nilius,
The Ca2+-activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5-biphosphate.
2006,
Pubmed
Nimigean,
Electrostatic tuning of ion conductance in potassium channels.
2003,
Pubmed
,
Xenbase
Ogielska,
Cooperative subunit interactions in C-type inactivation of K channels.
1995,
Pubmed
,
Xenbase
Panyi,
C-type inactivation of a voltage-gated K+ channel occurs by a cooperative mechanism.
1995,
Pubmed
Perraud,
ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology.
2001,
Pubmed
Rohacs,
Regulation of transient receptor potential (TRP) channels by phosphoinositides.
2007,
Pubmed
Rohács,
PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain.
2005,
Pubmed
Sano,
Immunocyte Ca2+ influx system mediated by LTRPC2.
2001,
Pubmed
Sauer,
Protein interactions central to stabilizing the K+ channel selectivity filter in a four-sited configuration for selective K+ permeation.
2011,
Pubmed
Starkus,
The calcium-permeable non-selective cation channel TRPM2 is modulated by cellular acidification.
2010,
Pubmed
Suh,
Electrostatic interaction of internal Mg2+ with membrane PIP2 Seen with KCNQ K+ channels.
2007,
Pubmed
Takahashi,
Roles of TRPM2 in oxidative stress.
2011,
Pubmed
Tóth,
Identification of direct and indirect effectors of the transient receptor potential melastatin 2 (TRPM2) cation channel.
2010,
Pubmed
,
Xenbase
Whorton,
Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium.
2011,
Pubmed
,
Xenbase
Yang,
State-dependent inhibition of TRPM2 channel by acidic pH.
2010,
Pubmed