T-type calcium channel regulation by specific G-protein betagamma subunits.
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 secretion. 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 signals, yet these signals have not been identified. Here we show that the inhibition of alpha1H (Ca(v)3.2), but not alpha(1G) (Ca(v)3.1) LVA Ca2+ channels is mediated selectively by beta2gamma2 subunits that bind to the intracellular loop connecting channel transmembrane domains II and III. This region of the alpha1H channel is crucial for inhibition, because its replacement abrogates inhibition and its transfer to non-modulated alpha1G channels confers beta2gamma2-dependent inhibition. betagamma reduces channel activity independent of voltage, a mechanism distinct from the established betagamma-dependent inhibition of non-L-type high-voltage-activated channels of the Ca(v)2 family. These studies identify the alpha1H channel as a new effector for G-protein betagamma subunits, and highlight the selective signalling roles available for particular betagamma combinations.
Wolfe
Joshua T
JT
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
Wang
Hongge
H
Howard
Jason
J
Garrison
James C
JC
Barrett
Paula Q
PQ
D020816:Amino Acid Motifs; D002121:Calcium Channel Blockers / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials; D021122:Protein Subunits / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
C121855:CACNA1G protein, human; C479952:CACNA1H protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D021122:Protein Subunits; D017447:Receptors, Dopamine D1; D011993:Recombinant Fusion Proteins; D000242:Cyclic AMP; D020962:Heterotrimeric GTP-Binding Proteins