Signaling mechanisms of D2, D3, and D4dopamine receptors determined in transfected cell lines
The receptors in the dopamine D2-receptor subfamily-D2, D3, and D4- translate the signal transmitted by dopamine into a program of intracellular changes. These changes are mediated by various members of the G-protein superfamily. We have used cloned receptor expression systems to evaluate the signaling systems that can be activated by these receptors. Inhibition of cAMP is one signaling pathway that appears to be activated by stimulation of all three receptor subtypes. The NaH-1 exchanger is also activated by stimulation of the D2-receptor subtype, with lesser effects seen after D4- and D3-receptor stimulation. The net effect of such activation is an increase in the rate of extracellular acidification. Stimulation of protein kinase A (PKA) selectively desensitizes D3and D4, but not D2, activation of the NaH-1 exchanger. Similarly, although both D2and D4activation potentiate ATP-stimulated arachidonic acid release, agents that activate PKA affect only the D2-mediated response. Activation of D2, D3, and D4receptors stimulates mitogenesis, with the degree of stimulation dependent on receptor type. D2receptors transiently stimulate the phosphorylation of mitogen-activated protein kinases; the effects of the other receptor subtypes are not yet known. All of the D2-, D3-, and D4-mediated intracellular changes are sensitive to pertussis toxin, indicating the involvement of a G(i) or G(o) signal transduction protein. Therefore, D2, D3, and D4receptors may control multiple signaling events.
Lajiness, ME; Chio, CL; Huff, RM; Caron, MG; Tamminga, CA; Van Tol, HHM; Carlsson, A; Schwartz, JC; Piercey, MF
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