Regulators of G Protein Signaling Attenuate the G Protein–mediated Inhibition of N-Type Ca Channels

Karim Melliti; Ulises Meza; Rory Fisher; Brett Adams

doi:10.1085/jgp.113.1.97

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Regulators of G Protein Signaling Attenuate the G Protein–mediated Inhibition of N-Type Ca Channels

Journal article

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Regulators of G Protein Signaling Attenuate the G Protein–mediated Inhibition of N-Type Ca Channels

Karim Melliti, Ulises Meza, Rory Fisher and Brett Adams

The Journal of general physiology, Vol.113(1), pp.97-110

01/01/1999

DOI: 10.1085/jgp.113.1.97

PMCID: PMC2222986

PMID: 9874691

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Abstract

Regulators of G protein signaling (RGS) proteins bind to the α subunits of certain heterotrimeric G proteins and greatly enhance their rate of GTP hydrolysis, thereby determining the time course of interactions among Gα, Gβγ, and their effectors. Voltage-gated N-type Ca channels mediate neurosecretion, and these Ca channels are powerfully inhibited by G proteins. To determine whether RGS proteins could influence Ca channel function, we recorded the activity of N-type Ca channels coexpressed in human embryonic kidney (HEK293) cells with G protein–coupled muscarinic (m2) receptors and various RGS proteins. Coexpression of full-length RGS3T, RGS3, or RGS8 significantly attenuated the magnitude of receptor-mediated Ca channel inhibition. In control cells expressing α1B, α2, and β3 Ca channel subunits and m2 receptors, carbachol (1 μM) inhibited whole-cell currents by ∼80% compared with only ∼55% inhibition in cells also expressing exogenous RGS protein. A similar effect was produced by expression of the conserved core domain of RGS8. The attenuation of Ca current inhibition resulted primarily from a shift in the steady state dose–response relationship to higher agonist concentrations, with the EC 50 for carbachol inhibition being ∼18 nM in control cells vs. ∼150 nM in RGS-expressing cells. The kinetics of Ca channel inhibition were also modified by RGS. Thus, in cells expressing RGS3T, the decay of prepulse facilitation was slower, and recovery of Ca channels from inhibition after agonist removal was faster than in control cells. The effects of RGS proteins on Ca channel modulation can be explained by their ability to act as GTPase-accelerating proteins for some Gα subunits. These results suggest that RGS proteins may play important roles in shaping the magnitude and kinetics of physiological events, such as neurosecretion, that involve G protein–modulated Ca channels.

muscarinic receptors

voltage-gated calcium channel

presynaptic inhibition

regulator of G protein signaling proteins

neurosecretion

Details

Title: Subtitle: Regulators of G Protein Signaling Attenuate the G Protein–mediated Inhibition of N-Type Ca Channels
Creators: Karim Melliti - From the
Ulises Meza - From the
Rory Fisher - From the
Brett Adams - From the
Resource Type: Journal article
Publication Details: The Journal of general physiology, Vol.113(1), pp.97-110
DOI: 10.1085/jgp.113.1.97
PMID: 9874691
PMCID: PMC2222986
NLM abbreviation: J Gen Physiol
ISSN: 0022-1295
eISSN: 1540-7748
Publisher: The Rockefeller University Press
Language: English
Date published: 01/01/1999
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040433502771

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