Dopamine D1receptor signaling: Does GαQ-phospholipase C actually play a role?

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Despite numerous studies showing therapeutic potential, no central dopamine D1receptor 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 D1ligand might overcome some of the past limitations. SKF-83959 [6-chloro-3- methyl-1-(m-tolyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8- diol] is reported to be a highly biased D1ligand, having full agonism at D1-mediated activation of phospholipase C (PLC) signaling (viaGαQ) and antagonism at D1-mediated adenylate cyclase signaling (via GαOLF/S). For this reason, numerous studies have used this compound to elucidate the physiologic role of D1-PLC signaling, including a novel molecular mechanism (GαQ-PLC activation via D1-D2heterodimers). There is, however, contradictory literature that suggests that SKF-83959 is actually a partial agonist at both D1-mediated adenylate cyclase and β-arrestin recruitment. Moreover, the D1-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 D1partial 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 D1receptors. 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 D1signaling.

Original languageEnglish (US)
Pages (from-to)9-17
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Oct 1 2014

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology


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