Document Detail

The calcium-permeable non-selective cation channel TRPM2 is modulated by cellular acidification.
MedLine Citation:
PMID:  20194125     Owner:  NLM     Status:  MEDLINE    
TRPM2 is a calcium-permeable non-selective cation channel expressed in the plasma membrane and in lysosomes that is critically involved in aggravating reactive oxygen species (ROS)-induced inflammatory processes and has been implicated in cell death. TRPM2 is gated by ADP-ribose (ADPR) and modulated by physiological processes that produce peroxide, cyclic ADP-ribose (cADPR), nicotinamide adenine dinucleotide phosphate (NAADP) and Ca(2+). We investigated the role of extra- and intracellular acidification on heterologously expressed TRPM2 in HEK293 cells. Our results show that TRPM2 is inhibited by external acidification with an IC(50) of pH 6.5 and is completely suppressed by internal pH of 6. Current inhibition requires channel opening and is strongly voltage dependent, being most effective at negative potentials. In addition, increased cytosolic pH buffering capacity or elevated [Ca(2+)](i) reduces the rate of current inactivation elicited by extracellular acidification, and Na(+) and Ca(2+) influence the efficacy of proton-induced inactivation. Together, these results suggest that external protons permeate TRPM2 channels to gain access to an intracellular site that regulates channel activity. Consistent with this notion, single-channel measurements in HEK293 cells reveal that internal protons induce channel closure without affecting single-channel conductance, whereas external protons affect channel open probability as well as single-channel conductance of native TRPM2 in neutrophils. We conclude that protons compete with Na(+) and Ca(2+) for channel permeation and channel closure results from a competitive antagonism of protons at an intracellular Ca(2+) binding site.
John G Starkus; Andrea Fleig; Reinhold Penner
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-03-01
Journal Detail:
Title:  The Journal of physiology     Volume:  588     ISSN:  1469-7793     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-16     Completed Date:  2010-07-29     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1227-40     Citation Subset:  IM    
University of Hawaii, Pacific Biosciences Research Center, Queens Medical Center, University Tower, 814, 1356 Lusitania Street, Honolulu, HI 96813, USA.
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MeSH Terms
Calcium / metabolism*
Cell Membrane / metabolism
Cell Membrane Permeability / physiology*
Cells, Cultured
Hydrogen-Ion Concentration
Kidney / cytology,  metabolism*
Lysosomes / metabolism
Patch-Clamp Techniques
TRPM Cation Channels / metabolism*
Grant Support
Reg. No./Substance:
0/TRPM Cation Channels; 0/TRPM2 protein, human; 7440-70-2/Calcium
Comment In:
J Physiol. 2010 May 15;588(Pt 10):1661-2   [PMID:  20472899 ]

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