Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels

Anne Laure Perraud, Christina L. Takanishi, Betty Shen, Shin Kang, Megan K. Smith, Carsten Schmitz, Heather M. Knowles, Dana Ferraris, Weixing Li, Jie Zhang, Barry L. Stoddard, Andrew M. Scharenberg

Research output: Contribution to journalArticle

Abstract

TRPM2 is a member of the transient receptor potential melastatin-related (TRPM) family of cation channels, which possesses both ion channel and ADP-ribose hydrolase functions. TRPM2 has been shown to gate in response to oxidative and nitrosative stresses, but the mechanism through which TRPM2 gating is induced by these types of stimuli is not clear. Here we show through structure-guided mutagenesis that TRPM2 gating by ADP-ribose and both oxidative and nitrosative stresses requires an intact ADP-ribose binding cleft in the C-terminal nudix domain. We also show that oxidative/ nitrosative stress-induced gating can be inhibited by pharmacological reagents predicted to inhibit NAD hydrolysis to ADP-ribose and by suppression of ADP-ribose accumulation by cytosolic or mitochondrial overexpression of an enzyme that specifically hydrolyzes ADP-ribose. Overall, our data are most consistent with a model of oxidative and nitrosative stress-induced TRPM2 activation in which mitochondria are induced to produce free ADP-ribose and release it to the cytosol, where its subsequent accumulation induces TRPM2 gating via interaction within a binding cleft in the C-terminal NUDT9-H domain of TRPM2.

Original languageEnglish (US)
Pages (from-to)6138-6148
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number7
DOIs
StatePublished - Feb 18 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels'. Together they form a unique fingerprint.

  • Cite this

    Perraud, A. L., Takanishi, C. L., Shen, B., Kang, S., Smith, M. K., Schmitz, C., Knowles, H. M., Ferraris, D., Li, W., Zhang, J., Stoddard, B. L., & Scharenberg, A. M. (2005). Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels. Journal of Biological Chemistry, 280(7), 6138-6148. https://doi.org/10.1074/jbc.M411446200