ReviewCellular mechanisms that determine selective RGS protein regulation of G protein-coupled receptor signaling
Introduction
Neurotransmitters and hormones rely upon receptors (G protein-coupled receptors; GPCRs) and heterotrimeric G proteins to exert their actions on target cells. In recent years, our understanding of G protein-coupled receptor (GPCR) signaling and pharmacology has become increasingly more complex. Though early models of GPCR signaling proposed that effector activation occurred primarily through a linear pathway (i.e. receptor, G protein, effector) [1], newer models indicate that numerous receptor- and G protein-binding partners exist to modulate signaling at each level [2], [3], [4]. Regulators of G protein signaling (RGS proteins) are among the most prominent of these newly appreciated binding partners.
RGS proteins (>30 family members) are defined by a shared 120 amino acid domain that binds directly to activated Gα subunits to attenuate G protein signaling [5], [6], [7]. Growing evidence indicates that RGS proteins act as tightly regulated modulators and integrators of G protein signaling [7]. The RGS protein superfamily is classified into six distinct subfamilies based on amino acid sequence identities and overall protein structure [5], [6]. These include: A/RZ (prototype, or pt = RGSZ), B/R4 (pt RGS4), C/R7 (pt RGS7), D/R12 (pt RGS12), E/RA (pt Axin), and F/RL (RGS-like proteins such as RhoGEFs, AKAPs, GRKs and RGS/PX1). Members of the C/R7, D/R12, E/RA and F/RL are large complex proteins (60–160 kDa) with variable N- and C-termini containing domains that bind additional signaling proteins.
Although much is known today regarding the molecular basis for RGS/Gα interactions ([6] and references therein), relatively little is known about how RGS selectivity for target receptors and/or G protein signaling pathways is determined in living cells. Recent findings indicate that GPCRs recruit a growing list of non-G protein binding partners that serve regulatory and/or novel signaling roles [3], [4]. Emerging models of GPCR signaling suggest that receptors can serve as platforms for scaffolding proteins that assemble multi-protein complexes with shared signaling functions. In this review, we discuss recent findings indicating that RGS proteins not only interact with Gα proteins and effectors, but that RGS proteins also can selectively interact (directly or indirectly) with GPCRs to preferentially regulate signal transduction pathways (Table 1).
Section snippets
Early evidence that RGS proteins form functional pairs with preferred receptors
Following the realization that RGS proteins comprise a large and diverse family, early speculation predicted that individual RGS proteins bound preferentially to certain classes of Gα subunits. Indeed, a certain degree of specificity appears to be built into the RGS and Gα contact faces [8], [9], [10], [11]. For example, most members of the B/R4 subfamily of small, simple RGS proteins (RGS1-5, 8, 13, 16, and 18) interact indiscriminately with members of the Gi/oα and/or Gq/11α subfamilies as
Direct and selective RGS interactions with GPCRs
The first reported direct interaction of an RGS protein with a GPCR involved RGS12 and the interleukin-8 receptor, CXCR2 [23]. RGS12 is unique among RGS family members in that one splice variant contains both an N-terminal and a complementary C-terminal PDZ binding motif. RGS12 binding to CXCR2 was found to be mediated by the RGS12 PDZ domain interaction with a specific compatible PDZ binding motif on the receptor C-tail. However, the physiological relevance of this interaction remains
Intermediate scaffolding proteins determine selective RGS/GPCR coupling
Scaffolding proteins that bind directly to certain RGS proteins and GPCRs have been described. The RGS-interacting protein, GIPC (GAIP-interacting protein, C terminus), contains a PDZ domain that interacts directly with a complementary binding motif present in the C-terminal domain of RGS19/GAIP [28]. Several GPCRs have been reported to bind GIPC since its identification, including β1 adrenergic [29], D2 and D3 dopamine [30], [31], and hLHR receptors [32], suggesting that GIPC potentially acts
Receptors as signaling platforms that recruit a unique constellation of regulatory proteins
The discovery that RGS proteins form selective functional pairs with GPCRs has profound implications on our understanding of GPCR signaling and regulation. As we have discussed in this review, certain RGS proteins have the capacity to bind either the i3 loops or the C-terminal tails of GPCRs, regions that have been shown to be critically important in the binding of signaling partners, such as the G protein heterotrimer, and desensitization machinery such as GRKs and arrestins. The next
Summary and perspectives
As we have outlined in this review, increasing evidence supports the notion that RGS proteins serve critical roles in GPCR signaling and regulation, and that this occurs through a physical and functional coupling between RGS and GPCR. Emerging models of GPCR signaling suggest that receptors serve as unique signaling platforms that assemble various signaling and regulatory proteins that allow for selective activation and termination of particular signaling pathways, and that RGS proteins may be
Acknowledgments
K.L.N. is supported by a Ruth L. Kirschstein NRSA Postdoctoral Training Fellowship (1 F32 GM075450-01). J.R.H. is supported by RO1 grants from the National Institutes of Health (NS37112 and GM61847).
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