title: TRPM channels modulate epileptic-like convulsions via systemic ion homeostasis.
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. The Caenorhabditis elegans locomotor circuit operates via coordinated activity of cholinergic excitatory and GABAergic inhibitory transmission. We have previously shown that a gain-of-function mutation in a neuronal acetylcholine receptor, acr-2(gf), causes an epileptic-like convulsion behavior. 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 Zn(2+). 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.
authors.affiliation: Division of Biological Sciences, Section of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Tamara M
authors.initials: TM
authors.lastname: Stawicki
authors.forename: Keming
authors.initials: K
authors.lastname: Zhou
authors.forename: John
authors.initials: J
authors.lastname: Yochem
authors.forename: Lihsia
authors.initials: L
authors.lastname: Chen
authors.forename: Yishi
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D004594:Electrophysiology; D006706:Homeostasis / Q000502:physiology*; D007477:Ions / Q000378:metabolism*; D007814:Larva / Q000502:physiology; D008274:Magnesium; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D050053:TRPM Cation Channels / Q000235:genetics*
chemical_list: C098140:Acr-2 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C554835:GTL-2 protein, C elegans; D007477:Ions; D011978:Receptors, Nicotinic; D050053:TRPM Cation Channels; D008274:Magnesium