Opinion
Neuronal Gq/11-coupled dopamine receptors: an uncharted role for dopamine

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There is strong evidence for the existence of Gq/11-coupled dopamine receptors in the brain but the mechanism by which dopamine signaling activates Gq/11, or its roles in neuronal function, are only just beginning to be understood. The importance of such a pathway is underlined by putative links between dopamine-regulated phosphoinositide signaling and several central nervous system disorders that include schizophrenia, addiction and Parkinson's disease.

Introduction

The importance of neurotransmission through the G-protein-coupled receptors for dopamine is well established, with fundamental roles for these receptors demonstrated for a wide variety of neuronal processes that underlie learning, cognition, emotion, motor function and reward. Furthermore, dysregulation of dopaminergic neurotransmission in the brain has been implicated in disorders such as schizophrenia, drug addiction, attention deficit hyperactivity disorder and Parkinson's disease. Accordingly, dopamine receptors have been the subject of intense efforts to delineate the full complement of signaling pathways mediated by individual receptor subtypes, the contributions of each of these pathways to various neuronal functions and their relationships to the aforementioned disorders.

Although signaling through each of the five mammalian dopamine receptors (D1–D5) is traditionally associated with stimulation (D1, D5) or inhibition (D2–D4) of adenylyl cyclase (AC) through Gs/olf or Gi/o proteins, respectively, evidence has mounted for additional signaling cascades initiated by dopamine receptor activation, including those mediated by associated Gβγ subunits, Gz proteins and Gq/11 proteins [1]. The coupling of dopamine receptors to phosphatidylinositol [PtdIns (PI)] metabolism and intracellular calcium release through activation of Gq/11 is of particular interest because, despite an accumulating body of literature describing the existence of Gq/11-coupled dopamine receptors and their putative links to neuropsychiatric disease, the molecular identity of these signaling complexes and their neurobiological relevance is still the subject of debate. The identification of such complexes and a greater understanding of how Gq/11 activation by dopamine contributes to neuronal function is important not only for our knowledge of how dopamine exerts its effects in the brain, but also for our understanding of dopamine-related disorders and our view of potential targets for drug development in these conditions.

Section snippets

Gq/11-coupled dopamine receptors in brain

Activation of PtdIns metabolism is a well established mechanism of receptor-mediated signal transduction that includes the enzymatic action of phospholipase C (PLC) on phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2 (PIP2)] to produce diacylglycerol (DAG) and inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3 (IP3)], the latter of which can activate intracellular Ins(1,4,5)P3 receptors to release intracellular calcium. Early examination of potential links between dopamine receptor activation

Molecular identity of the neuronal Gq/11-coupled dopamine receptor

The ability of different benzazepine D1 receptor agonists to stimulate AC and PLC differentially (Figure 1), in addition to inducing distinct behavioral phenotypes [14], has provided strong evidence that the neuronal Gq/11-coupled dopamine receptor is a distinct entity from the Gs-coupled D1 receptor. However, the potential for a degree of promiscuity of these D1 agonists, in addition to several contradictory findings, have prevented consensual agreement regarding the identity of the

A D1–D2 dopamine receptor hetero-oligomer that is coupled to Gq/11

The ability of receptors to hetero-oligomerize raised the possibility that Gq/11 activation by the D1 receptor was enabled by obligatory coincident activation of another associated receptor – namely, the D2 receptor. Myriad functional interactions between activated D1 and D2 receptors have been described, including potentiation of immediate early gene expression [24], potentiation of arachidonic acid release [25] and sensitization to the effects of cocaine [26]. Accordingly, it was recently

Multiple dopamine receptor complexes coupled to Gq/11 activation?

The identification of a Gq/11-coupled signaling unit composed of D1 and D2 receptors presents a novel mechanism by which dopamine can exert its effects in the brain, and seems to answer long-standing questions not only about the identity of the Gq/11-coupled dopamine receptor, but also about the nature of some of the synergistic interactions between these two receptors, which normally have diametrically opposed effects on the AC signaling pathway. However, the results showing Gq/11 activation

Implications for neuronal function and disease

It is only recently that the implications of a dopamine receptor signaling pathway linked to intracellular calcium homeostasis in neurons are beginning to be understood. Intracellular calcium signaling is known to have a crucial role in almost all aspects of neuronal function, including gene expression, protein activity and regulation of synaptic transmission [33]. Evidence has indicated that Gq/11-coupled dopamine receptors might have a prominent role in synaptic plasticity by its ability to

Concluding remarks

The vast majority of functional studies on neuronal dopamine receptors have focused on the consequences of their ability to modulate AC activity. The importance of PtdIns signaling by dopamine receptors has not been adequately addressed, in part owing to a limited ability to identify and specifically modulate this pathway in experimental preparations. The identification of the D1–D2 hetero-oligomer as a modulator of Gq/11 activity provided the first definitive mechanism for linking dopamine

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