Volume 271, Number 37, Issue of September 13, 1996 pp. 22297-22300
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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COMMUNICATION:
Activation of a Mitogen-activated Protein Kinase (ERK2) by the 5-Hydroxytryptamine_1A Receptor Is Sensitive Not Only to Inhibitors of Phosphatidylinositol 3-Kinase, but to an Inhibitor of Phosphatidylcholine Hydrolysis

(Received for publication, July 2, 1996)

Daniel S. Cowen , Rebecca S. Sowers and David R. Manning

From the Departments of Pharmacology and  Psychiatry at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084

A variety of receptors coupled to GTP-binding regulatory proteins (G proteins) initiate signals that culminate in activation of the mitogen-activated protein kinases ERK1 and ERK2. We demonstrate here that the human 5-HT_1A receptor expressed in Chinese hamster ovary cells similarly promotes activation of ERK1 and ERK2, but that the pathway used does not conform entirely to those proposed previously for G protein-coupled receptors. Activation of ERK2 by the 5-HT_1A receptor-selective agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT) was inhibited completely by pertussis toxin and substantially by prolonged treatment of cells with phorbol 12-myristate 13-acetate. The implied requirement for protein kinase C, however, was negated in studies with bisindolylmaleimide and Ro-31-8220, which, although completely inhibiting activation of ERK2 by phorbol ester, had no impact on activation by 8-OH-DPAT. The anticipated inhibition by the tyrosine kinase inhibitors genistein and herbimycin A, moreover, was marginal at best. As expected for a G_i-coupled receptor, the inhibitors of phosphatidylinositol 3-kinase wortmannin and LY294002 inhibited activation of ERK2, albeit only partly (70%). Of significance, an inhibitor of a phosphatidylcholine-specific phospholipase C, tricyclodecan-9-yl-xanthogenate (D609), caused a similar degree of inhibition. When the two types of inhibitors were combined, an almost complete inhibition was achieved. Our data suggest that phosphatidylinositol 3-kinase and phosphatidylcholine-specific phospholipase C represent components of different, but partly overlapping pathways that can account almost entirely for the activation of ERK2 by the 5-HT_1A receptor.

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