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Cannabinoid CB1 Receptor-Mediated Inhibition of Prolactin Release and Signaling Mechanisms in GH₄C₁ Cells¹

Department of Pharmacology and Toxicology, University of North Dakota (B.Y.H., L.L.C.), Grand Forks, North Dakota 58203; Department of Anesthesiology, Medical College of Wisconsin (A.S., Z.J.B., W.M.K.), Milwaukee, Wisconsin 53226; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences (P.L.P.), Little Rock, Arkansas 72205; and College of Pharmacy and Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati Medical Center (A.R.B.), Cincinnati, Ohio 45069

Address all correspondence and requests for reprints to: Dr. Begonia Ho, Department of Pharmacology, University of North Dakota, 501 North Columbia Road, Grand Forks, North Dakota 58203-2817. E-mail: bho{at}badlands.nodak.edu

The GH₄C₁ cell line was used to study the cellular mechanisms of cannabinoid-mediated inhibition of PRL release. Cannabinoid CB1 receptor activation inhibited vasoactive intestinal polypeptide- and TRH-stimulated PRL release, but not its basal secretion. The cannabinoid-mediated inhibition of TRH-stimulated PRL release was reversed by the CB1 receptor-specific antagonist, SR141,716A, and was abolished by pertussis toxin pretreatment, indicating that G subunits belonging to the G_i and G_o family were involved in the signaling. Photoaffinity labeling using [-³²P]azidoaniline GTP showed that cannabinoid receptor stimulation in cell membranes produced activation of four G subunits (G_i2, G_i3, G_o1, and G_o2), which was also reversed by SR141,716A. The CB1 receptor agonists, WIN55,212–2 and CP55,940, inhibited cAMP formation and calcium currents in GH₄C₁ cells. The subtypes of calcium currents inhibited by WIN55,212–2 were characterized using holding potential sensitivity and calcium channel blockers. WIN55,212–2 inhibited the -conotoxin GVIA (Conus geographus)- and -agatoxin IVA (Aigelenopsis aperta)-sensitive calcium currents, but not the nisoldipine-sensitive calcium currents, suggesting the inhibition of N- and P-type, but not L-type, calcium currents. Taken together, the present findings indicate that CB1 receptors can couple through pertussis toxin-sensitive G subunits to inhibit adenylyl cyclase and calcium currents and suppress PRL release from GH₄C₁ cells.

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