Dopamine D1 Receptor Signaling: Does GαQ-Phospholipase C Actually Play a Role?

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-1H-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 (viaG alpha(Q)) and antagonism at D-1-mediated adenylate cyclase signaling (via G alpha(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 alpha(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 beta-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.