D-1-LIKE DOPAMINERGIC ACTIVATION OF PHOSPHOINOSITIDE HYDROLYSIS IS INDEPENDENT OF D-1A DOPAMINE-RECEPTORS - EVIDENCE FROM D-1A KNOCKOUT MICE

Accumulated evidence suggests that dopamine and dopamine D-1 agonists can activate phospholipase C in both brain and peripheral tissue. The receptor that mediates the hydrolysis of phosphoinositides has not bee n identified. The cloned dopamine D-1A receptor that is generally thou ght to be linked to adenylyl cyclase, has also been proposed to couple to phospholipase C. However, a number of studies have suggested that this signaling pathway is mediated via a distinct D-1-like dopamine re ceptor. We tested whether the D-1A site plays a role in stimulating ph osphoinositide hydrolysis by using the dopamine D-1A-deficient mutant mice as a test model. Results show that although D-1 dopamine receptor -mediated production of cAMP is completely absent in membranes of D-1A -deficient mice, D-1 receptor-mediated accumulation of inositol phosph ate is identical in tissues of mutant and wild-type animals. Furthermo re, the coupling of [H-3]SCH23390 binding sites in striatal or frontal cortex membranes to G(alpha s) is markedly reduced, although coupling of [H-3]SCH23390 binding sites to G(alpha q) was unaltered in tissue taken from D-1A mutant mice compared with control animals. These resul ts clearly demonstrate that dopaminergic stimulation of inositol phosp hate formation is mediated by a D-1 dopamine receptor subtype that is distinct from the D-1A receptor that activates adenylyl cyclase.