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The Journal of Neuroscience, April 15, 1998, 18(8):2834-2841
Protein Kinase C Disrupts Cannabinoid Actions by Phosphorylation of the CB1 Cannabinoid Receptor
D. E. Garcia1, 3, S. Brown2, B. Hille1, and K. Mackie1, 2 Departments of 1 Physiology and Biophysics and 2 Anesthesiology, University of Washington, Seattle, Washington 98195, and 3 Departamento de Fisiologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, CP 04510 Mexico DF, Mexico
We have found that phosphorylation of a G-protein-coupled receptor by protein kinase C (PKC) disrupts modulation of ion channels by the receptor. In AtT-20 cells transfected with rat cannabinoid receptor (CB1), the activation of an inwardly rectifying potassium current (Kir current) and depression of P/Q-type calcium channels by cannabinoids were prevented by stimulation of protein kinase C by 100 nM phorbol 12-myristate 13-acetate (PMA). In contrast, activation of Kir current by somatostatin was unaffected, and inhibition of calcium channels was only modestly attenuated. The possibility that PKC acted by phosphorylating CB1 receptors was confirmed by demonstrating that PKC phosphorylated a single serine (S317) of a fusion protein incorporating the third intracellular loop of CB1. Mutating this serine to alanine did not affect the ability of CB1 to modulate currents, but it eliminated disruption by PMA, demonstrating that PKC can disrupt ion channel modulation by receptor phosphorylation.
Key words: cannabinoid; G-protein-coupled receptor; calcium channel; inwardly rectifying potassium channel; protein kinase C; phosphorylation
Copyright © 1998 Society for Neuroscience 0270-6474/98/1882834-08$05.00/0
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