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The Journal of Neuroscience, June 15, 1998, 18(12):4521-4531

The  Subunit of G_q Contributes to Muscarinic Inhibition of the M-Type Potassium Current in Sympathetic Neurons

Jane E. Haley¹, Fe C. Abogadie¹, Patrick Delmas¹, Mariza Dayrell¹, Yvonne Vallis¹, Graeme Milligan³, Malcolm P. Caulfield², David A. Brown¹, and Noel J. Buckley¹

¹ Wellcome Laboratory for Molecular Pharmacology, Department of Pharmacology, University College London, London, WC1E 6BT, United Kingdom, ² Department of Pharmacology and Neuroscience, Neurosciences Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom, and ³ Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom

Rat superior cervical ganglion (SCG) neurons express low-threshold noninactivating M-type potassium channels (I_K(M)), which can be inhibited by activation of M1 muscarinic receptors. This inhibition occurs via pertussis toxin-insensitive G-proteins belonging to the G_q family (). We have used DNA plasmids encoding antisense sequences against the 3' untranslated regions of G subunits (antisense plasmids) to investigate the specific G-protein subunits involved in muscarinic inhibition of I_K(M). These antisense plasmids specifically reduced levels of the target G-protein 48 hr after intranuclear injection. In cells depleted of G_q, muscarinic inhibition of I_K(M) was attenuated compared both with uninjected neurons and with neurons injected with an inappropriate G_oA antisense plasmid. In contrast, depletion of G₁₁ protein did not alter I_K(M) inhibition. To determine whether the  or subunits of the G-protein mediated this inhibition, we have overexpressed the C terminus of  adrenergic receptor kinase 1 (ARK1), which binds free subunits. ARK1 did not reduce muscarinic inhibition of I_K(M) at a concentration of plasmid that can reduce -mediated inhibition of calcium current (). Also, expression of ₁₂ dimers did not alter the I_K(M) density in SCG neurons. In contrast, I_K(M) was virtually abolished in cells expressing GTPase-deficient, constitutively active forms of G_q and G₁₁. These data suggest that G_q is the principal mediator of muscarinic I_K(M) inhibition in rat SCG neurons and that this more likely results from an effect of the  subunit than the subunits of the G_q heterotrimer.

Key words: M-current; G-protein; antisense; muscarinic receptor; superior cervical ganglion neuron; adrenergic receptor kinase

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18124521-11$05.00/0

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