Ras-Dependent Activation of Fibroblast Mitogen-Activated Protein Kinase by 5-HT1A Receptor via a G Protein βγ-Subunit-Initiated Pathway

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Abstract
Serotonin (5-HT) is a potent mitogen in many cells types, an action which is frequently mediated through pertussis toxin-sensitive G proteins. In the current study, we used pharmacological inhibitors and dominant negative signaling constructs to delineate elements which participate in the activation of MAPK, a growth-associated mitogen-activated protein kinase, by human G protein-coupled 5-HT1A receptor transfected into CHO-K1 cells in a stable manner. The activation pathway does not directly involve phorbol ester-sensitive protein kinase C types, but does require (i) pertussis toxin-sensitive G protein βγ-subunits, (ii) a staurosporine- and genistein-sensitive protein kinase, (iii) phosphoinositide-3‘-kinase activity, (iv) activation of Sos in a multimolecular complex that contains p46Shc and p52Shc, and Grb2, (v) the GTPase p21Ras, and (vi) the protein kinase p74Raf-1. These data demonstrate that the 5-HT1A receptor mediates MAPK activity by convergence upon a common activation pathway that is shared with receptor tyrosine kinases.

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