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Vol. 302, Issue 3, 1105-1112, September 2002

Increased Dopamine Receptor Signaling and Dopamine Receptor-G Protein Coupling in Denervated Striatum

Guoping Cai, Hoau-Yan Wang and Eitan Friedman

Department of Physiology and Pharmacology, The City University of New York Medical School, New York, New York

Chronic interruption of the nigrostriatal dopaminergic pathway leads to sensitized dopaminergic responses in striatum. We attempted to explore the mechanism(s) underlying this dopaminergic supersensitivity by assessing dopamine receptor signaling and receptor-G protein coupling in unilateral 6-hydroxydopamine-lesioned rats. Dopamine-stimulated adenylyl cyclase activity as well as dopamine-activated guanosine 5'-O-(3-[35S]thiotriphosphate) ([35S]GTPgamma S) binding and [3H]palmitate incorporation by Galpha proteins were enhanced in tissues obtained from denervated striata without apparent changes in Galpha protein levels. Moreover, high-affinity binding sites of the D1 dopamine receptor increased in lesioned compared with control striata without altering the expression level of the receptor. These denervation-mediated changes appear to correlate with the increase in D1 dopamine receptor binding sites that co-immunoprecipitated with Galpha s(olf)/q(11) proteins. In contrast, the total number of D2 receptor binding sites was increased, yielding an increase in absolute number of high-affinity sites without significant changes in the proportion of high-affinity sites. Stimulation of the D2 dopamine receptor enhanced coupling to Galpha i protein; this was increased in the striata lesioned. The results provide an important molecular mechanism by which dopamine receptor-regulated signaling is enhanced following denervation of dopaminergic input to striatum. Although D1 dopamine receptor supersensitivity appears to be mediated by enhanced coupling of the receptor to its G proteins, sensitization in the D2 dopamine receptor system is mediated by increased D2 receptor density and enhanced D2 receptor-Gi protein coupling.

0022-3565/02/3023-1105$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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