TRPM channels modulate epileptic-like convulsions via systemic ion homeostasis

Tamara M. Stawicki, Keming Zhou, John Yochem, Lihsia Chen, Yishi Jin

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Neuronal networks operate over a wide range of activity levels, with both neuronal and nonneuronal cells contributing to the balance of excitation and inhibition. Activity imbalance within neuronal networks underlies many neurological diseases, such as epilepsy [1]. The Caenorhabditis elegans locomotor circuit operates via coordinated activity of cholinergic excitatory and GABAergic inhibitory transmission [2]. We have previously shown that a gain-of-function mutation in a neuronal acetylcholine receptor, acr-2(gf), causes an epileptic-like convulsion behavior [3]. Here we report that the behavioral and physiological effects of acr-2(gf) require the activity of the TRPM channel GTL-2 in nonneuronal tissues. Loss of gtl-2 function does not affect baseline synaptic transmission but can compensate for the excitation-inhibition imbalance caused by acr-2(gf). The compensatory effects of removing gtl-2 are counterbalanced by another TRPM channel, GTL-1, and can be recapitulated by acute treatment with divalent cation chelators, including those specific for Zn2+. Together, these data reveal an important role for ion homeostasis in the balance of neuronal network activity and a novel function of nonneuronal TRPM channels in the fine-tuning of this network activity.

Original languageEnglish (US)
Pages (from-to)883-888
Number of pages6
JournalCurrent Biology
Volume21
Issue number10
DOIs
StatePublished - May 24 2011

Bibliographical note

Funding Information:
We thank Takayuki Teramoto and Eric Lambie for gtl-2 cDNA constructs and strains, Erik Jorgensen and Ken Miller for reporter lines, and H. Robert Horvitz for support and guidance during initial acr-2(gf) suppressor analysis. Additional strains were provided from the National BioResource Project in Japan and the Caenorhabditis Genetic Center; the latter is supported by grants from NIH. We greatly appreciate the advice on electrophysiology by Zhitao Hu, Josh Kaplan, and Maelle Jospin. We thank Andrew Chisholm, Darwin Berg, and members of our laboratories, especially Emma Garren and B. Yingchun Qi, for discussions and comments on the manuscript. This work was supported by a UCSD Chancellor's interdisciplinary award to T.M.S., as well as NIH grants (NS035546 to Y.J. and NS045873 to L.C.). Y.J. is an investigator of HHMI.

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