Regulation of T-type calcium channels by Rho-associated kinase.

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 Ca(v)3.1 and Ca(v)3.3 channels without affecting the voltage dependence of activation or inactivation, whereas Ca(v)3.2 currents showed depolarizing shifts in these parameters. LPA-induced inhibition of Ca(v)3.1 was dependent on intracellular GTP, and was antagonized by treatment with ROCK and RhoA inhibitors, LPA receptor antagonists or GDPssS. Site-directed mutagenesis of the Ca(v)3.1 alpha1 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 Ca(v)3.2 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.

journal_name

Nat Neurosci

journal_title

Nature neuroscience

authors

Iftinca M,Hamid J,Chen L,Varela D,Tadayonnejad R,Altier C,Turner RW,Zamponi GW

doi

10.1038/nn1921

subject

Has Abstract

pub_date

2007-07-01 00:00:00

pages

854-60

issue

7

eissn

1097-6256

issn

1546-1726

pii

nn1921

journal_volume

10

pub_type

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