Editors' ChoiceCalcium Channels

Calcium Channels Get ROCKed

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Science's STKE  03 Jul 2007:
Vol. 2007, Issue 393, pp. tw233
DOI: 10.1126/stke.3932007tw233

Three distinct α1 subunit genes encode T-type Ca2+ channels (CaV3.1, CaV3.2, and CaV3.3), and these have nonredundant roles in pain transmission, cell proliferation, and cardiovascular function. Lysophosphatidic acid (LPA), a phospholipid involved in the development and growth of neurons, binds to members of a family of G protein-coupled receptors (GPCRs) called LPA1-5, of which LPA1 is the most abundant in the brain. LPA1 activates members of the Gαi, Gαq, and Gα12/13 family of G proteins. Stimulated Gα12/13 activates the Rho guanosine triphosphatase family member RhoA, which activates Rho-associated kinase (ROCK). ROCK isoforms phosphorylate (among other substrates) sodium and potassium channels. Previous studies have shown overlapping physiological responses to activation of either ROCK or T-type Ca2+ channels, so Iftinca et al. investigated a role for ROCK in regulating T-type Ca2+ channels. Whole-cell patch clamp assays on tsA-201 cells (a subclone of HEK 293 cells) transiently expressing rat CaV3.1 showed a dose-dependent decrease in channel current in response to LPA. Experiments with pertussis toxin (to block Gαi) and protein kinase C inhibitors (to block signals downstream of Gαq) suggested that the Gα12/13 pathway mediated the inhibitory effect of LPA on CaV3.1 activity. Coexpression of dominant-negative mutants of Gα12 and Gα13, or treatment with specific inhibitors of Rho or ROCK, substantially decreased the inhibitory effects of LPA. Mutation of Ser and Thr residues in putative ROCK-phosphorylation consensus sites (found between domains II and III) of CaV3.1 resulted in mutant channels that did not respond to LPA. These consensus sites are conserved in all T-type Ca2+ channels, and the authors found that whereas LPA treatment also inhibited the activity of CaV3.3, it increased the activity of CaV3.2. The authors performed experiments in neurons isolated from the lateral habenula (LHb) nucleus (predominantly expressing CaV3.1) and the dorsal root ganglia (DRG, in which CaV3.2 is the major channel) of rats and found that the effects of LPA (decreasing currents in LHb neurons and increasing currents in the DRG) were all blocked by inhibition of ROCK. Together, these data describe a new mechanism of regulation of the activity of T-type Ca2+ channels and, given that T-type Ca2+ channels and ROCK are coexpressed in other cell types, suggest that this regulation might be important for various physiological processes.

M. Iftinca, J. Hamid, L. Chen, D. Varela, R. Tadayonnejad, C. Altier, R. W. Turner, G. W. Zamponi, Regulation of T-type calcium channels by Rho-associated kinase. Nat. Neurosci. 10, 854-860 (2007). [PubMed]

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