Abstract

Several neurotransmitters that act through G protein-linked receptors have been shown to affect the growth rate of dividing cells. An analysis of the early signaling events that mediate this response revealed some novel activities for G protein-linked receptors. Activation of D2 receptors heterologously expressed in CHO cells also stimulates the synthesis of DNA, which results in increased proliferation. Pertussis toxin pretreatment abolishes D2 agonist-stimulated mitogenesis, which indicates the need for a G protein. D2 receptor-stimulated mitogenesis occurs in the presence of a membrane-soluble cyclic AMP analog and, in Chinese hamster ovary cells with a mutated protein kinase A, which is resistant to the growth effects of cyclic AMP. Therefore, the proliferative response is independent of changes in cyclic AMP. It was determined that a number of other signaling pathways commonly used by Gi-linked receptors are not involved in the D2-mediated mitogenic response. These include arachidonic acid release, stimulation of protein kinase C, stimulation of inositol phosphates, opening of K+ channels and activation of amiloride sensitive Na+/H+ exchange. D2 receptor-stimulated mitogenesis is blocked by genistein, a tyrosine kinase inhibitor, at the same concentrations that block thrombin-stimulated mitogenesis. In fact, dopamine and thrombin stimulate a rapid increase in tyrosine phosphorylation of a number of substrates in the transfected Chinese hamster ovary cells. These results reveal a novel signaling event for D2 dopamine receptors, activation of tyrosine phosphorylations. They suggest the importance of these events for D2 dopamine receptor-stimulated mitogenesis.