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

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 (viaGα_Q) and antagonism at D₁-mediated adenylate cyclase signaling (via Gα_OLF/S). For this reason, numerous studies have used this compound to elucidate the physiologic role of D₁-PLC signaling, including a novel molecular mechanism (Gα_Q-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.