Stargazin modulates neuronal voltage-dependent Ca2+ channel Cav2.2 by a Gβγ-dependent mechanism

Isabella Tselnicker*, Vladimir A. Tsemakhovich, Carmen W. Dessauer, Nathan Dascal

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Loss of neuronal protein stargazin (γ2) is associated with recurrent epileptic seizures and ataxia in mice. Initially, due to homology to the skeletal muscle calcium channel γ1 subunit, stargazin and other family members (γ3-8) were classified as γ subunits of neuronal voltage-gated calcium channels (such as CaV2.1-Ca V2.3). Here, we report that stargazin interferes with G protein modulation of CaV2.2 (N-type) channels expressed in Xenopus oocytes. Stargazin counteracted the Gβγ-induced inhibition of Ca V2.2 channel currents, caused either by coexpression of the Gβγ dimer or by activation of a G protein-coupled receptor. Expression of high doses of Gβγ overcame the effects of stargazin. High affinity Gβγ scavenger proteins m-cβARK and m-phosducin produced effects similar to stargazin. The effects of stargazin and m-cβARK were not additive, suggesting a common mechanism of action, and generally independent of the presence of the CaVβ3 subunit. However, in some cases, coexpression of CaVβ3 blunted the modulation by stargazin. Finally, the Gβγ-opposing action of stargazin was not unique to CaV2.2, as stargazin also inhibited the Gβγ-mediated activation of the G protein-activated K+ channel. Purified cytosolic C-terminal part of stargazin bound Gβγ in vitro. Our results suggest that the regulation by stargazin of biophysical properties of CaV2.2 are not exerted by direct modulation of the channel but via a Gβγ-dependent mechanism.

Original languageEnglish
Pages (from-to)20462-20471
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number27
DOIs
StatePublished - 2 Jul 2010

Funding

FundersFunder number
National Institute of General Medical SciencesR01GM060419

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