Trends in Pharmacological Sciences
ReviewEmerging roles for RGS proteins in cell signalling
Section snippets
RGS interactions with Gα subunits
Gα subunits act as molecular switches that bind and hydrolyse GTP, and the lifetime of the active Gα–GTP species and associated signalling event is dictated by the lifetime of the GTP–Gα complex. Many drugs mimic the actions of neurotransmitters or hormones by binding at cell-surface receptors to regulate GTP binding on Gα. As negative regulators, RGS proteins could affect Gα by acting as inhibitors of GDP release to prevent GTP binding, or as GTPase-activating proteins (GAPs) to limit the
RGS proteins modulate hormone and neurotransmitter signalling
Early studies showing RGS-mediated attenuation of G-protein signalling in simple organisms predicted that their mammalian counterparts would likely play important roles in regulating receptor signalling3, 4, 5. Consistent with this idea are reports showing that RGS proteins markedly alter hormone- and neurotransmitter-stimulated cellular responses in mammalian cells. These include modulation of adenylate cyclase activity53, inhibition of mitogen activated protein kinase (MAPK)12, 41 and
RGS membrane localization and interactions with hormone receptors
Nearly all RGS proteins are predicted to be cytosolic proteins, yet their apparent site of action is adjacent to G proteins at the plasma membrane. Many family members are tightly associated with membranes, and cellular mechanisms that contribute to RGS membrane targeting have been identified. In the simplest model, cytosolic RGS proteins are recruited to the plasma membrane by activated Gα subunits, as has been shown for RGS4 (Ref. 62). Other cellular mechanisms are also important for placing
RGS protein binding partners
Proteins that are not Gα subunits have been identified as binding partners for RGS proteins (Fig. 4). These include proteins directly involved in G-protein signalling as well as other unexpected proteins with diverse cellular functions. As discussed, RGS12 is the only family member reported to contain a PDZ domain that binds with high affinity to a four amino acid PDZ binding motif (STTL) at the IL-8B tail66. GRKs directly phosphorylate certain GPCRs to block receptor signalling and engage
Are some RGS proteins G-protein-regulated effectors?
p115RhoGEF is not the first or only example of a signalling protein that is both a GAP and effector for its Gα partner (Fig. 5). Phospholipase Cβ (PLCβ) is activated by Gqα family members to regulate inositol lipid signalling and PLCβ is an effective GAP and negative regulator of Gqα function81. The γ-subunit of cGMP-phosphodiesterase (PDEγ) is sequestered by transducin Gα (Gtα) to free the PDE catalytic subunits that regulate retinal cGMP levels and visual signalling. PDEγ, in concerted action
Implications for RGS proteins in human health and disease
Given their broad roles in cell signalling, RGS proteins could contribute to the development and progression of certain human diseases and there is evidence to suggest that some RGS proteins associate directly with proteins implicated in specific disease states (Table 2). RGS7 interacts with the polycystin protein, which is mutated in 85% of patients with autosomal-dominant polycystic kidney disease44. Axin and conductin bind directly to the APC protein, an apparent tumour suppressor linked to
Future directions
RGS proteins are a highly diverse collection of signalling proteins. That these proteins silence G-protein-signalling pathways while also engaging other signalling proteins provides a compelling reason to explore additional physiological functions. Important goals for future study include the determination of cellular roles for currently recognized RGS-protein-binding partners, identification of additional binding partners and their cellular functions, and determination of the functional
Acknowledgements
The author would like to apologize to those investigators whose work could not be cited or discussed due to the breadth of the topic and space limitations. JRH would like to thank J. M. Bunge for timely aid and ministrations and Ken Blumer, Susanne Hollinger, Rick Kahn, Maurine Linder, Jeremy Rose and Julie Saugstad for helpful discussions and comments on the manuscript. JRH is supported by the National Institutes of Health NINDS RO1NS37112, the American Heart Association, GA Affiliate, and the
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