Article abstract
Nature Neuroscience 10, 854 - 860 (2007)
Published online: 10 June 2007 | doi:10.1038/nn1921
Regulation of T-type calcium channels by Rho-associated kinase
Mircea Iftinca1,2,3, Jawed Hamid1,2,3, Lina Chen1,2,3, Diego Varela1,2,3, Reza Tadayonnejad1,2, Christophe Altier1,2,3, Ray W Turner1,2 & Gerald W Zamponi1,2,3
Abstract
We investigated the regulation of T-type channels by Rho-associated kinase (ROCK). Activation of ROCK via the endogenous ligand lysophosphatidic acid (LPA) reversibly inhibited the peak current amplitudes of rat Cav3.1 and Cav3.3 channels without affecting the voltage dependence of activation or inactivation, whereas Cav3.2 currents showed depolarizing shifts in these parameters. LPA-induced inhibition of Cav3.1 was dependent on intracellular GTP, and was antagonized by treatment with ROCK and RhoA inhibitors, LPA receptor antagonists or GDP
S. Site-directed mutagenesis of the Cav3.1 
1 subunit revealed that the ROCK-mediated effects involve two distinct phosphorylation consensus sites in the domain II-III linker. ROCK activation by LPA reduced native T-type currents in Y79 retinoblastoma and in lateral habenular neurons, and upregulated native Cav3.2 current in dorsal root ganglion neurons. Our data suggest that ROCK is an important regulator of T-type calcium channels, with potentially far-reaching implications for multiple cell functions modulated by LPA.
- Hotchkiss Brain Institute, Departments of Physiology & Biophysics, University of Calgary, 3330 Hospital Drive N.W., Calgary, T2N 4N1, Canada
- Cell Biology & Anatomy, University of Calgary, 3330 Hospital Drive N.W., Calgary, T2N 4N1, Canada
- Pharmacology & Therapeutics, University of Calgary, 3330 Hospital Drive N.W., Calgary, T2N 4N1, Canada.
Correspondence to: Gerald W Zamponi1,2,3 e-mail: zamponi@ucalgary.ca
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