Abstract
Accumulated evidence suggests that dopamine and dopamine D1agonists can activate phospholipase C in both brain and peripheral tissue. The receptor that mediates the hydrolysis of phosphoinositides has not been identified. The cloned dopamine D1A receptor that is generally thought 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 D1-like dopamine receptor. We tested whether the D1A site plays a role in stimulating phosphoinositide hydrolysis by using the dopamine D1A-deficient mutant mice as a test model. Results show that although D1 dopamine receptor-mediated production of cAMP is completely absent in membranes of D1A-deficient mice, D1 receptor-mediated accumulation of inositol phosphate is identical in tissues of mutant and wild-type animals. Furthermore, the coupling of [3H]SCH23390 binding sites in striatal or frontal cortex membranes to Gαs is markedly reduced, although coupling of [3H]SCH23390 binding sites to Gαq was unaltered in tissue taken from D1A mutant mice compared with control animals. These results clearly demonstrate that dopaminergic stimulation of inositol phosphate formation is mediated by a D1 dopamine receptor subtype that is distinct from the D1A receptor that activates adenylyl cyclase.
Footnotes
- Received August 13, 1996.
- Accepted October 9, 1996.
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Send reprint requests to: Eitan Friedman, Ph.D., Department of Pharmacology, MCP-Hahnemann University School of Medicine, 3200 Henry Avenue, Philadelphia, PA 19129. E-mail:friedmane{at}allegheny.edu
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This work was supported by United States Public Health Service Grant NS29514 from the National Institute of Neurological Disorders and Stroke. J.D. is supported by a Basser Fellowship from the Royal Australasian College of Physicians. L.-Q.J. is supported by a predoctoral stipend from Allegheny-Single Research Institute Neuroscience Program.
- The American Society for Pharmacology and Experimental Therapeutics
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