The role of the regulatory guanine nucleotide binding proteins (G proteins) in the development of dopamine (DA) receptor supersensitivity was studied in striatal membranes from reserpine treated rats. [α-32P]GTP labeled two striatal proteins with molecular masses of 45 and 40 kD. These proteins were previously identified as alpha subunits of G(s) and G(i)/G(o), respectively. Seven days of reserpine treatment caused a 43% increase in steady-state basal [α-32P]GTP binding to striatal G(αs). Basal [α- 32P]GTP binding to the 40-kD protein band was unchanged by reserpine treatment. Incubation of membranes with DA stimulated [α-32P]GTP binding to both protein bands. Although 10 μM DA stimulated guanine nucleotide binding to G(αs) and G(αi/o) in control tissue by 317% and 236%, respectively, the increases in [α-32P]GTP binding in the reserpine- treated animals were 482% (P < .01) and 366% (P < .01), respectively. A single injection of reserpine did not alter basal or DA-stimulated [α- 32P]GTP binding. Repeated reserpine treatment also enhanced serotonin- induced stimulation of [α-32P]GTP binding to striatal G(αi/o) but not to G(αs). However, carbachol-stimulated binding was unaffected by the treatment. Reserpine treatment did not change membrane G(αs), G(αi 1/2 ) or G(αo) levels, as assessed by immunoblotting or by toxin-catalyzed ADP ribosylation. These results suggest that increases in both basal and receptor-mediated activations of G proteins are associated with the development of reserpine-induced striatal DA receptor supersensitivity. This mechanism appears to be of particular importance to mediate the supersensitivity of the D1 DA receptor, which develops during repeated treatment with reserpine.
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1994|