When Two Receptors Are Different from One

Science's STKE  24 Aug 2004:
Vol. 2004, Issue 247, pp. tw299
DOI: 10.1126/stke.2472004tw299

The D1 and D2 types of dopamine receptors are members of distinct subfamilies but appear to act together in a number of systems where combinations of specific agonists produce distinct biological effects from those produced by D1- or D2-specific agonists alone. Lee et al. now propose that this may reflect the fact that D1 and D2 receptors physically interact, and in doing so produce distinct signals not mediated by either receptor alone. D1 and D2 receptors are G protein-coupled receptors that signal predominantly through Gs or Golf, or Gi or Go, respectively, to adenylyl cyclase. However when both D1 and D2 dopamine receptors were stably expressed in cultured cells, treatment of the cells with a combination of D1- and D2-selective agonists caused a rapid increase in the intracellular concentration of free calcium ([Ca2+]i). The increase in ([Ca2+]i) was prevented when cells were treated with the phospholipase C inhibitor U73122 and was not present if cells were treated with only one of the agonists or if cells expressed only one of the receptors. Immunohistochemical analysis of rat and human brain cells indicated that the D1 and D2 receptors are expressed and localized together in some cells. Furthermore, D2 receptors were detected by immunoblotting in association with D1 receptors immunoprecipitated from membranes of rat striatal neurons. Thus, the combination of D1 and D2 receptors appears to produce a signal (presumably through coupling to a new G protein, Gq, which then regulates phospholipase C) that is distinct from those produced by either receptor alone. Such behavior may underlie some of the diverse effects of dopamine in the brain.

S. P. Lee, C. H. So, A. J. Rashid, G. Varghese, R. Cheng, A. J. Lança, B. F. O'Dowd, S. R. George, Dopamine D1 and D2 receptor co-activation generates a novel phospholipase C-mediated calcium signal. J. Biol. Chem. 279, 35671-35678 (2004). [Abstract] [Full Text]