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beta gamma dimers derived from G(o) and G(i) proteins contribute different components of adrenergic inhibition of Ca2+ channels in rat sympathetic neurones

Delmas, P; Abogadie, FC; Milligan, G; Buckley, NJ; Brown, DA; (1999) beta gamma dimers derived from G(o) and G(i) proteins contribute different components of adrenergic inhibition of Ca2+ channels in rat sympathetic neurones. J PHYSIOL-LONDON , 518 (1) 23 - 36.

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Abstract

1. Using perforated-patch recordings, we have examined the part played by endogenous G-protein subunits: in the alpha(2)-adrenoceptor-mediated inhibition of N-type Ca2+ currents in sympathetic neurones.2. Two components of I-Ca inhibition by noradrenaline were recorded: a prominent, high affinity and voltage-dependent pertussis toxin (PTX)-sensitive pathway and a minor, low affinity and mostly voltage-insensitive PTS-resistant pathway.3. PTS-sensitive inhibition was reduced by microinjection of antibodies against either G alpha(oA,B) or G alpha(i1,2). The voltage-dependent fraction of inhibition was reduced by anti-G alpha(o) but not by anti-G alpha(1) antibody.4. Antisense depletion of G alpha(oA) led to a marked reduction of noradrenaline-induced inhibition and voltage dependence. By contrast, G alpha(i) depletion attenuated noradrenergic modulation without affecting the voltage dependence.5. Expression of the beta gamma-binding agents beta-adrenergic receptor kinase 1 (C-terminus, beta ARK1(C-ter)) or G alpha(i1) with a Cys3 to Ser mutation partially prevented noradrenergic inhibition while alpha-transducin abolished it. Residual inhibition was mostly voltage independent in cells expressing beta ARKI(C-ter) but was strongly reversed by depolarization in G alpha(i1) Cys3Ser-expressing cells.6. Expression of the PTX-resistant Ga-i1 Cys351Ile mutant in cells treated with PTX restored alpha(2)-adrenoceptor inhibition. This restored inhibition was weakly reversed by depolarization. Both the degree and voltage dependence of inhibition were correlated with the level of expression of the G alpha(il) Cys351Ile subunit.7. Our findings identify beta gamma dimers associated with G alpha(oA) and G alpha(i) as mediators of the PTX-sensitive alpha(2)-adrenoceptor-mediated inhibition of S-type Ca2+ channels. Different beta gamma combinations may account for the differential voltage-dependent effects of G(o) and G(i) on I-Ca.

Type: Article
Title: beta gamma dimers derived from G(o) and G(i) proteins contribute different components of adrenergic inhibition of Ca2+ channels in rat sympathetic neurones
Keywords: CALCIUM CHANNELS, VOLTAGE DEPENDENCE, COUPLED RECEPTORS, BINDING PROTEINS, ALPHA(1) SUBUNIT, PERTUSSIS TOXIN, MODULATION, ALPHA(2A)-ADRENOCEPTOR, PATHWAYS, NEUROTRANSMITTERS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/827
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