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The Journal of Neuroscience, February 1, 1998, 18(3):878-886

The Ca²⁺ Channel ₃ Subunit Differentially Modulates G-Protein Sensitivity of _1A and _1B Ca²⁺ Channels

John P. Roche and Steven N. Treistman

Department of Pharmacology and Molecular Toxicology, Program in Neuroscience, University of Massachusetts Medical School, Worcester, Massachusetts 01655

We have shown previously that the Ca²⁺ channel ₃ subunit is capable of modulating tonic G-protein inhibition of _1A and _1B Ca²⁺ channels expressed in oocytes. Here we determine the modulatory effect of the Ca²⁺ channel ₃ subunit on M₂ muscarinic receptor-activated G-protein inhibition and whether the ₃ subunit modulates the G-protein sensitivity of _1A and _1B currents equivalently. To compare the relative inhibition by muscarinic activation, we have used successive ACh applications to remove the large tonic inhibition of these channels. We show that the resulting rebound potentiation results entirely from the loss of tonic G-protein inhibition; although the currents are temporarily relieved of tonic inhibition, they are still capable of undergoing inhibition through the muscarinic pathway. Using this rebound protocol, we demonstrate that the inhibition of peak current amplitude produced by M₂ receptor activation is similar for _1A and _1B calcium currents. However, the contribution of the voltage-dependent component of inhibition, characterized by reduced inhibition at very depolarized voltage steps and the relief of inhibition by depolarizing prepulses, was slightly greater for the _1B current than for the _1A current. After co-expression of the ₃ subunit, the sensitivity to M₂ receptor-induced G-protein inhibition was reduced for both _1A and _1B currents; however, the reduction was significantly greater for _1A currents. Additionally, the difference in the voltage dependence of inhibition of _1A and _1B currents was heightened after co-expression of the Ca²⁺ channel ₃ subunit. Such differential modulation of sensitivity to G-protein modulation may be important for fine tuning release in neurons that contain both of these Ca²⁺ channels.

Key words: Ca²⁺ channels; G-proteins; _1A; _1B; Ca²⁺ channel  subunit; voltage-dependent inhibition; Xenopus oocyte; muscarinic M₂ receptor; NEM

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Copyright © 1998 Society for Neuroscience  0270-6474/98/183878-09$05.00/0

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