D2 DOPAMINE-RECEPTOR STIMULATION OF MITOGENESIS IN TRANSFECTED CHINESE-HAMSTER OVARY CELLS - RELATIONSHIP TO DOPAMINE STIMULATION OF TYROSINE PHOSPHORYLATIONS

Several neurotransmitters that act through G protein-linked receptors have been shown to affect the growth rate of dividing cells. An analys is of the early signaling events that mediate this response revealed s ome novel activities for G protein-linked receptors. Activation of D2 receptors heterologously expressed in CHO cells also stimulates the sy nthesis of DNA, which results in increased proliferation. Pertussis to xin pretreatment abolishes D2 agonist-stimulated mitogenesis, which in dicates the need for a G protein. D2 receptor-stimulated mitogenesis o ccurs 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 prolifer ative response is independent of changes in cyclic AMP. It was determi ned that a number of other signaling pathways commonly used by G(i)-li nked 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 act ivation 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 ph osphorylation of a number of substrates in the transfected Chinese ham ster ovary cells. These results reveal a novel signaling event for D2 dopamine receptors, activation of tyrosine phosphorylations. They sugg est the importance of these events for D2 dopamine receptor-stimulated mitogenesis.