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Dopamine D 1 Receptor Signaling: Does G α Q –Phospholipase C Actually Play a Role?

The Journal of Pharmacology and Experimental Therapeutics, ISSN: 0022-3565, Vol: 351, Issue: 1, Page: 9-17
2014
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Article Description

Despite numerous studies showing therapeutic potential, no central dopamine D 1 receptor ligand has ever been approved, because of potential limitations, such as hypotension, seizures, and tolerance. Functional selectivity has been widely recognized as providing a potential mechanism to develop novel therapeutics from existing targets, and a highly biased, functionally selective D 1 ligand might overcome some of the past limitations. SKF-83959 [6-chloro-3-methyl-1-( m -tolyl)-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine-7,8-diol] is reported to be a highly biased D 1 ligand, having full agonism at D 1 -mediated activation of phospholipase C (PLC) signaling (via G α Q ) and antagonism at D 1 -mediated adenylate cyclase signaling (via G α OLF/S ). For this reason, numerous studies have used this compound to elucidate the physiologic role of D 1 -PLC signaling, including a novel molecular mechanism (G α Q -PLC activation via D 1 -D 2 heterodimers). There is, however, contradictory literature that suggests that SKF-83959 is actually a partial agonist at both D 1 -mediated adenylate cyclase and β -arrestin recruitment. Moreover, the D 1 -mediated PLC stimulation has also been questioned. This Minireview examines 30 years of relevant literature and proposes that the data strongly favor alternate hypotheses: first, that SKF-83959 is a typical D 1 partial agonist; and second, that the reported activation of PLC by SKF-83959 and related benzazepines likely is due to off-target effects, not actions at D 1 receptors. If these hypotheses are supported by future studies, it would suggest that caution should be used regarding the role of PLC and downstream pathways in D 1 signaling.

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