Modulation of Ca2+ channels by G-protein beta gamma subunits.
Calcium ions entering cells through voltage-gated Ca2+ channels initiate rapid release of neurotransmitters and secretion of hormones. Ca2+ currents can be inhibited in many cell types by neurotransmitters acting through G proteins via a membrane-delimited pathway independently of soluble intracellular messengers. Inhibition is typically caused by a positive shift in the voltage dependence and a slowing of channel activation and is relieved by strong depolarization resulting in facilitation of Ca2+ currents. This pathway regulates the activity of N-type and P/Q-type Ca2+ channels, which are localized in presynaptic terminals and participate in neurotransmitter release. Synaptic transmission is inhibited by neurotransmitters through this mechanism. G-protein alpha subunits confer specificity in receptor coupling, but it is not known whether the G alpha or G beta gamma subunits are responsible for modulation of Ca2+ channels. Here we report that G beta gamma subunits can modulate Ca2+ channels. Transfection of G beta gamma into cells expressing P/Q-type Ca2+ channels induces modulation like that caused by activation of G protein-coupled receptors, but G alpha subunits do not. Similarly, injection or expression of G beta gamma subunits in sympathetic ganglion neurons induces facilitation and occludes modulation of N-type channels by noradrenaline, but G alpha subunits do not. In both cases, the G gamma subunit is ineffective by itself, but overexpression of exogenous G beta subunits is sufficient to cause channel modulation.
Herlitze
S
S
Department of Pharmacology, University of Washington, Seattle 98195, USA.
Garcia
D E
DE
Mackie
K
K
Hille
B
B
Scheuer
T
T
Catterall
W A
WA
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006150:Guanine Nucleotides / Q000378:metabolism; D015640:Ion Channel Gating; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000378:metabolism; D014162:Transfection
D015220:Calcium Channels; D006150:Guanine Nucleotides; D019204:GTP-Binding Proteins; D009638:Norepinephrine