Oxymetazoline inhibits adenylate cyclase by activation of serotonin-1 receptors in the OK cell, an established renal epithelial cell line.
The nonselective alpha-adrenergic agonist oxymetazoline inhibits parathyroid hormone (PTH)-stimulated cAMP production in intact OK cells, an epithelial cell line derived from an American opossum kidney. This inhibition, however, is not blocked by alpha 2-adrenergic receptor antagonists. After excluding several alternate hypotheses to explain this anomalous activity of oxymetazoline, we hypothesized that oxymetazoline activates a receptor in OK cells that is negatively coupled to adenylate cyclase but distinct from the alpha 2-adrenergic receptor. Prior exposure of OK cells to pertussis toxin blocks the inhibitory response to oxymetazoline, suggesting involvement of a guanine nucleotide-binding regulatory protein. Screening various compounds for attenuation of PTH-stimulated adenylate cyclase showed that serotonin (5HT) is a potent and fully efficacious agonist. Desensitization of alpha 2-receptor-mediated inhibition of cAMP production by epinephrine did not alter the response to either 5HT or oxymetazoline, indicating that these compounds do not produce their effect by activating alpha 2-adrenergic receptors. The 5HT1 receptor-selective antagonist methiothepin, but not ketanserin (5HT2-selective) or ICS-205,930 (5HT3-selective), blocked the response to both 5HT and oxymetazoline. The potency of methiothepin for antagonizing oxymetazoline-induced inhibition of PTH-stimulated cAMP production was not significantly different from its potency for the 5HT-induced effect. These data indicate that OK cells express a 5HT1 receptor that is negatively coupled to adenylate cyclase and that oxymetazoline is an agonist at these receptors.
Murphy
T J
TJ
Department of Pharmacology, School of Medicine, University of Missouri-Columbia 65212.
Bylund
D B
DB
D000067956:Adenylyl Cyclase Inhibitors; D001665:Binding Sites; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D008719:Methiothepin / Q000494:pharmacology; D010109:Oxymetazoline / Q000494:pharmacology*; D010281:Parathyroid Hormone / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D011985:Receptors, Serotonin / Q000032:analysis / Q000187:drug effects*
D000067956:Adenylyl Cyclase Inhibitors; D007093:Imidazoles; D010281:Parathyroid Hormone; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D008719:Methiothepin; D010109:Oxymetazoline; D000242:Cyclic AMP