ACTIVATION OF MICROTUBULE-ASSOCIATED PROTEIN-KINASE (ERK) AND P70 S6 KINASE BY D-2 DOPAMINE-RECEPTORS

The ability of human and rat D-2(short) and D-2(long) dopamine recepto rs to activate microtubule-associated protein (MAP) kinase (Erk1/2) an d p70 S6 kinase has been investigated in recombinant cells expressing these receptors. In cells expressing the D-2(short) receptor, dopamine activated both enzymes in a transient manner but with very different time courses, with activation of Erk being much quicker. Activation of both enzymes by dopamine was dose-dependent and could be prevented by a range of selective dopamine antagonists. Excellent correlations wer e observed between the potencies of the antagonists for blocking enzym e activation and their affinities for the D-2 dopamine receptor. Activ ation of Erk and of p70 S6 kinase via the D-2 dopamine receptors was p revented by pretreatment of the cells with pertussis toxin, indicating the involvement-of G proteins of the G(i) or G(o) family. Inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase) were found to block sub stantially, but not completely, activation of p70 S6 kinase by dopamin e, suggesting the involvement of PI 3-kinase-dependent and -independen t signalling pathways in its control by dopamine, p70 S6 kinase activa tion was completely blocked by rapamycin. In the case of Erk, activati on was partially blocked by wortmannin or LY294002, indicating a possi ble link with PI 3-kinase.