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The Journal of Neuroscience, December 20, 2006, 26(51):13373-13383; doi:10.1523/JNEUROSCI.3332-06.2006

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Cellular/Molecular
G-Proteins Modulate Cumulative Inactivation of N-Type (Ca_V2.2) Calcium Channels

Sarah McDavid¹ and Kevin P. M. Currie^1,2,3

Departments of ¹Anesthesiology and ²Pharmacology, and ³Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37232

Correspondence should be addressed to Kevin Currie, Departments of Anesthesiology and Pharmacology, Vanderbilt University Medical Center, T-4202 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2520. Email: Kevin.Currie{at}vanderbilt.edu

Precise regulation of N-type (Ca_V2.2) voltage-gated calcium channels (Ca-channels) controls many cellular functions including neurotransmitter and hormone release. One important mechanism that inhibits Ca²⁺ entry involves binding of G-protein ß subunits (Gß) to the Ca-channels. This shifts the Ca-channels from "willing" to "reluctant" gating states and slows activation. Voltage-dependent reversal of the inhibition (facilitation) is thought to reflect transient dissociation of Gß from the Ca-channels and can occur during high-frequency bursts of action potential-like waveforms (APW). Inactivation of Ca-channels will also limit Ca²⁺ entry, but it remains unclear whether G-proteins can modulate inactivation. In part this is because of the complex nature of inactivation, and because facilitation of Ca-channel currents (I_Ca) masks the extent and kinetics of inactivation during typical stimulation protocols. We used low-frequency trains of APW to activate I_Ca. This more closely mimics physiological stimuli and circumvents the problem of facilitation which does not occur at 5 Hz. Activation of endogenous G-proteins reduced both Ca²⁺-dependent, and voltage-dependent inactivation of recombinant I_Ca in human embryonic kidney 293 cells. This was mimicked by expression of wild-type Gß, but not by a point mutant of Gß with reduced affinity for Ca-channels. A similar decrease in the inactivation of I_Ca was produced by P2Y receptors in adrenal chromaffin cells. Overall, our data identify and characterize a novel effect of G-proteins on I_Ca, and could have important implications for understanding how G-protein-coupled receptors control Ca²⁺ entry and Ca²⁺-dependent events such as neurotransmitter and hormone release.

Key words: calcium current; G-protein; patch clamp; inactivation; neuromodulation; GPCR; N-type; calcium; inhibition

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Received Aug. 2, 2006; revised Nov. 3, 2006; accepted Nov. 21, 2006.

Correspondence should be addressed to Kevin Currie, Departments of Anesthesiology and Pharmacology, Vanderbilt University Medical Center, T-4202 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2520. Email: Kevin.Currie{at}vanderbilt.edu

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eLetters:

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The Beta-Gamma Dimer of G-Proteins Slows Down N-type Calcium Channel Inactivation

Norbert Weiss

J. Neurosci. Online, 17 Jan 2007 [Full text]

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