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Research ArticleMinireviews

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

Sang-Min Lee, Yang Yang and Richard B. Mailman
Journal of Pharmacology and Experimental Therapeutics October 2014, 351 (1) 9-17; DOI: https://doi.org/10.1124/jpet.114.214411
Sang-Min Lee
Departments of Pharmacology (S.-M.L., Y.Y., R.B.M.) and Neurology (Y.Y., R.B.M.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania
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Yang Yang
Departments of Pharmacology (S.-M.L., Y.Y., R.B.M.) and Neurology (Y.Y., R.B.M.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania
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Richard B. Mailman
Departments of Pharmacology (S.-M.L., Y.Y., R.B.M.) and Neurology (Y.Y., R.B.M.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania
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Abstract

Despite numerous studies showing therapeutic potential, no central dopamine D1 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 D1 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 D1 ligand, having full agonism at D1-mediated activation of phospholipase C (PLC) signaling (via GαQ) 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-D2 heterodimers). 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 D1 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 D1 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 D1 signaling.

Footnotes

    • Received June 2, 2014.
    • Accepted July 21, 2014.
  • This work was supported, in part, by the National Institutes of Health National Institute of Mental Health [Grants U01-MH082441 and R01-MH040537]; and by a Pennsylvania Keystone Innovation Grant.

  • R.B.M. has interests in issued and pending patents related to dopamine D1 receptor mechanisms that constitute a conflict of interest for which there is university oversight. The remaining authors declare no conflicts of interest.

  • dx.doi.org/10.1124/jpet.114.214411.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 1
1 Oct 2014
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Research ArticleMinireviews

Dopamine D1 Receptors and PLC

Sang-Min Lee, Yang Yang and Richard B. Mailman
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 9-17; DOI: https://doi.org/10.1124/jpet.114.214411

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Research ArticleMinireviews

Dopamine D1 Receptors and PLC

Sang-Min Lee, Yang Yang and Richard B. Mailman
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 9-17; DOI: https://doi.org/10.1124/jpet.114.214411
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  • Article
    • Abstract
    • The Potential Utility of a Functionally Selective D1 Ligand
    • SKF-83959, the First Functionally Selective D1 Ligand?
    • Hypothesis: SKF-83959 Is a Selective, High-Affinity D1 Ligand
    • Hypothesis: SKF-83959 Has No Intrinsic Activity at D1-Mediated Stimulation of Adenylate Cyclase
    • Hypothesis: SKF-83959 Activates PLC via a D1-GαQ Mechanism
    • Hypothesis: D1-D2 Heterodimer–Mediated Activation of GαQ-PLC-Ca2+ by D1-Selective Ligands Is an Important Signaling Mechanism
    • Hypothesis: D1-PLC Signaling of SKF-83959 Causes Novel Behavioral Effects
    • Reconciliation of the Role of D1 Receptors and GαQ-PLC Activation
    • Conclusions
    • Acknowledgments
    • Authorship Contributions
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    • Abbreviations
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