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T-type calcium channel regulation by specific G-protein βγ subunits

Abstract

Low-voltage-activated (LVA) T-type calcium channels have a wide tissue distribution and have well-documented roles in the control of action potential burst generation and hormone secretion1. In neurons of the central nervous system and secretory cells of the adrenal and pituitary, LVA channels are inhibited by activation of G-protein-coupled receptors that generate membrane-delimited signals2,3,4,5, yet these signals have not been identified. Here we show that the inhibition of α1H (Cav3.2), but not α1G (Cav3.1) LVA Ca2+ channels is mediated selectively by β2γ2 subunits that bind to the intracellular loop connecting channel transmembrane domains II and III. This region of the α1H channel is crucial for inhibition, because its replacement abrogates inhibition and its transfer to non-modulated α1G channels confers β2γ2-dependent inhibition. βγ reduces channel activity independent of voltage, a mechanism distinct from the established βγ-dependent inhibition of non-L-type high-voltage-activated channels of the Cav2 family6,7. These studies identify the α1H channel as a new effector for G-protein βγ subunits, and highlight the selective signalling roles available for particular βγ combinations.

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Figure 1: Effect of G-protein βγ expression on α1H and α1G Ca2+ currents.
Figure 2: Characterization of channel inhibition induced by β2γ2.
Figure 3: The α1H channel II–III loop supports β2γ2 binding and contributes to G-protein-dependent inhibition.
Figure 4: Effect of dopamine D1-receptor activation on wild-type and chimaeric T-type Ca2+ channels.

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Acknowledgements

We thank E. Perez-Reyes for α1H and α1G clones, the University of Virginia Flow-Cytometry Core for FACS analysis, and G. MacCleery for help with βγ purification. This study was supported by grants (to P.Q.B. and J.C.G.) from the NIH. J.T.W. was supported by predoctoral fellowships from the University of Virginia Cardiovascular Research Center and the American Heart Association.

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Correspondence to Paula Q. Barrett.

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Wolfe, J., Wang, H., Howard, J. et al. T-type calcium channel regulation by specific G-protein βγ subunits. Nature 424, 209–213 (2003). https://doi.org/10.1038/nature01772

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