Increases in guanine nucleotide binding to striatal G proteins is associated with dopamine receptor supersensitivity
Butkerait, P.; Wang, H.Y.; Friedman, E.
Journal of Pharmacology and Experimental Therapeutics 271(1): 422-428
1994
ISSN/ISBN: 0022-3565 PMID: 7965743 Document Number: 427313
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. (alpha-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 (alpha-32P)GTP binding to striatal G-alpha-s. Basal (alpha-32P)GTP binding to the 40-kD protein band was unchanged by reserpine treatment. Incubation of membranes with DA stimulated (alpha-32P)GTP binding to both protein bands. Although 10 mu-M DA stimulated guanine nucleotide binding to G-alpha-s and G-alpha-i/o in control tissue by 317% and 236%, respectively, the increases in (alpha-32P)GTP binding in the reserpine-treated animals were 482% (P lt .01) and 366% (P lt .01), respectively. A single injection of reserpine did not alter basal or DA-stimulated (alpha-32P)GTP binding. Repeated reserpine treatment also enhanced serotonin-induced stimulation of (alpha-32P)GTP binding to striatal G-alpha-i/o but not to G-alpha-s. However, carbachol-stimulated binding was unaffected by the treatment. Reserpine treatment did not change membrane G-alpha-s, G-alpha-i/2 or G-alpha-o 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 D-1 DA receptor, which develops during repeated treatment with reserpine.