Elsevier

Cellular Signalling

Volume 18, Issue 2, February 2006, Pages 135-150
Cellular Signalling

Review
Cell signalling diversity of the Gqα family of heterotrimeric G proteins

https://doi.org/10.1016/j.cellsig.2005.08.004Get rights and content

Abstract

Many receptors for neurotransmitters and hormones rely upon members of the Gqα family of heterotrimeric G proteins to exert their actions on target cells. Gα subunits of the Gq class of G proteins (Gqα, G11α, G14α and G15/16α) directly link receptors to activation of PLC-β isoforms which, in turn, stimulate inositol lipid (i.e. calcium/PKC) signalling. Although Gqα family members share a capacity to activate PLC-β, they also differ markedly in their biochemical properties and tissue distribution which predicts functional diversity. Nevertheless, established models suggest that Gqα family members are functionally redundant and that their cellular responses are a result of PLC-β activation and downstream calcium/PKC signalling. Growing evidence, however, indicates that Gqα, G11α, G14α and G15/16α are functionally diverse and that many of their cellular actions are independent of inositol lipid signalling. Recent findings show that Gqα family members differ with regard to their linked receptors and downstream binding partners. Reported binding partners distinct from PLC-β include novel candidate effector proteins, various regulatory proteins, and a growing list of scaffolding/adaptor proteins. Downstream of these signalling proteins, Gqα family members exhibit unexpected differences in the signalling pathways and the gene expression profiles they regulate. Finally, genetic studies using whole animal models demonstrate the importance of certain Gqα family members in cardiac, lung, brain and platelet functions among other physiological processes. Taken together, these findings demonstrate that Gqα, G11α, G14α and G15/16α regulate both overlapping and distinct signalling pathways, indicating that they are more functionally diverse than previously thought.

Introduction

Many hormones, neurotransmitters and sensory stimuli elicit cellular responses through the targeted activation of cell surface receptors coupled to Gq family G proteins. The Gq family members, Gq, G11, G14, and G15/16, like all heterotrimeric G proteins, are composed of three subunits, Gα, Gβ and Gγ, that cycle between inactive and active signalling states in response to guanine nucleotides [1], [2]. These membrane-bound proteins are engaged and activated by G protein-coupled receptors (GPCRs) for the GTP-dependent transduction of extracellular signals into cellular responses. The receptor-bound conformation of the G protein favors the displacement of GDP with GTP on the Gα subunit and induces dissociation of the heterotrimer subunits from the receptor and from each other. Gα-GTP and the Gβγ dimer then transmit the receptor-generated signals to downstream effector molecules and protein binding partners until the intrinsic GTPase activity of Gα hydrolyzes GTP to GDP and the inactive subunits reassociate.

The canonical effector molecules of activated, GTP-bound Gq family Gα subunits are the β-isoforms of phospholipase C (PLC-β). Gqα, G11α, G14α, and G15/16α (mouse/human orthologues, respectively) bind and stimulate PLC-β enzymes to initiate inositol lipid signalling. PLC-β enzymes catalyze the hydrolysis of the minor membrane phospholipid phosphatidylinositol bisphosphate, PIP2, to release inositol trisphosphate (IP3) and diacylglycerol (DAG) [3]. These second messengers serve to propagate and amplify the Gα-mediated signal with calcium mobilization following release from IP3-regulated intracellular stores and DAG-mediated stimulation of protein kinase C (PKC) [4], [5]. Inositol lipids, DAG, PKC and calcium each participate in multiple signalling networks and in this way link Gqα family members to a host of different cellular events [6].

Receptors coupled to Gqα, G11α, G14α, and G15/16α mediate a wide range of diverse, and sometimes divergent, cellular responses. Cell growth and proliferation, neuronal signalling, hematopoietic cell differentiation, leukocyte activation, platelet aggregation, glucose secretion, actin cytoskeleton reorganization, and smooth muscle contraction are among the physiological processes affected by Gqα family signalling. Although established models indicate that actions of receptors linked to Gqα family members are mediated by inositol lipid signalling [2], [7], [8], [9], growing evidence suggests that these pathways alone do not account for many Gqα-mediated responses. Rather, the extensive list of diverse cellular events that involve Gqα-linked signalling suggests that Gqα family members have complex roles in signal transduction which are not yet fully understood. Within this protein family, Gqα and G11α have been studied most extensively. Much less is understood about the functions of G14α and G15/16α, but based on their common capacities for PLC-β activation, they are generally assumed to be functionally similar to Gqα and G11α. Emerging evidence, however, indicates that Gqα family members are not functionally redundant, but instead have both shared and unique cellular roles. This review summarizes the divergent biochemical and biological properties of Gqα, G11α, G14α, and G15/16α and highlights the newly appreciated functional diversity of these important signalling mediators.

Section snippets

Tissue distribution

Gqα family members were first identified by affinity purification [10], [11] and molecular cloning strategies [12], [13]. Subsequent work demonstrated these proteins to be the much anticipated but previously unidentified G proteins that link receptors to activation of phospholipase C and inositol lipid signalling [14], [15], [16], [17], [18]. Further studies revealed that Gqα, G11α, G14α and G15/16α each have very different tissue and cell expression patterns (Table 1). Gqα and G11α mRNA and

Receptor coupling

Nearly 40% of all GPCRs rely upon Gqα family members to stimulate inositol lipid signalling [70]. These include more than 50 subtypes of receptors responsive to a range of hormones, neurotransmitters, neuropeptides, chemokines, autocrine and paracrine molecules [70]. Pertussis toxin (PTX) uncouples receptors from activation of Gi/o proteins, and Gβγ released from Gi/oα can stimulate PLC-β [3]. As such, GPCRs that activate inositol lipid signalling and calcium mobilization in a PTX-insensitive

Phospholipase C-β

The four isoforms of PLC-β (β1–β4) are stimulated directly and independently by Gα-GTP and Gβγ to hydrolyze PI(4,5)P2 and trigger inositol lipid signalling [3]. Activated Gqα family members stimulate all four PLC-β isoforms [113], [114], [115], [116]. In reconstitution assays, purified recombinant Gqα, G11α and G15/16α activated PLC-β isoforms with a similar rank order of potency (PLC-β1  PLC-β3  PLC-β2), with 10-fold greater potency for -β1 and -β3 over -β2 [114], [117], [118], [119], [120]. Gqα

Cell signalling diversity

We have summarized known binding partners for Gqα family members and, where information is available, the associated downstream signalling pathways. There also are many reports of signalling pathways and global cellular responses activated by Gqα family proteins in which the mediating Gα-effector protein(s) are unknown. Signalling downstream of these Gα involves diverse and complex kinase cascades that ultimately lead to regulated gene transcription and changes in cell physiology. Each Gqα

Physiological diversity

Many studies have established the physiological importance of Gqα family members, especially of the broadly expressed Gqα and G11α. So much has been uncovered regarding expression and signalling of these proteins under various conditions and in numerous cell types that this review cannot comprehensively summarize all the contributing work. Instead, we will focus on information gleaned from genetics studies in animals, as these studies indicate the global consequences of Gqα family activity on

Conclusion and future directions

We have outlined current evidence demonstrating the biochemical and cell signalling diversity among Gqα family members. Reported findings indicate that Gqα, G11α, G14α and G15/16α differ markedly with regard to their biochemical properties, tissue distribution, receptor coupling, protein binding partners, downstream cell signalling events, and organ physiology. Each of these differences reinforces the idea of cell signalling diversity, and challenges the established notions that Gqα family

Acknowledgements

The authors would like to thank Dr. Karen L. Neitzel for thoughtful comments and careful review of the manuscript. The authors are grateful to the National Institutes of Health (grants R01-NS37112 and R01-GM61847 to JRH) and to the American Heart Association predoctoral fellowship (grant 0515154B to KBH) for supporting our research related to this article.

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