Regulator G protein Signaling (RGS) proteins are critical components of the intracellular signaling pathways that mediate the effects of G protein-coupled receptors (GPCRs). Upon activation, GPCRs have conformational changes that allow the coupling and subsequent activation of the G-protein heterotrimeric complex (α, β, and γ); it is at this point when the RGS proteins play a key role in the deactivation of the alpha subunit contributing to the termination of the G protein-mediated signaling cascades[1, 2].
RGS proteins are a family with around 20 members characterized by the presence of a conserved RGS-homology (RH) domain. This domain contains the catalytic core that catalyzes the hydrolysis of guanosine triphosphate (GTP) to guanosine diphosphate of the G protein α subunit promoting the switch from activated to an inactivated state[3]. In addition to the RGS domain, RGS proteins also contain a range of other structural motifs that are critical for their function, including the G protein-binding domain, the DEP (Dishevelled, Egl-10 and Pleckstrin domain) domain, and the GoLoco motif[2, 3].
Role of RGS proteins in regulating GPCR signaling:
Recent studies have revealed that the interaction between RGS proteins and GPCRs is mediated by a range of structural motifs, including the G protein-binding (GB) and the RGS domains. The interaction between RGS proteins and GPCRs is highly specific and tightly regulated; mutations in the RGS domain and other structural motifs have been shown to alter the specificity and potency of the RGS-GPCR interaction[2].
As negative regulators of GPCR signaling, RGS proteins play a critical role in regulating the duration and amplitude of GPCR signaling. For example, μ opioid receptor (MOR) interacts with Gαi/o and Gαz subunits, which have a slow enzymatic GTPase activity requiring the action of RGSs proteins. RGSs bind to GTP-bound Gα to accelerate GTP hydrolysis reducing the activity of the Gα subunit and resulting in negative regulation of MOR downstream signaling[3, 4].
Besides the differences in their structural complexity, some members of the RGS family are selective for certain GPCRs, as a proof RGS4 which is expressed in the brain, has been shown to modulate dopamine signaling by specifically regulating the activity of the dopamine D2 receptor; enhancing the activity of the G protein that is coupled to the receptor and leading to a decrease in dopamine signaling[4, 5].
Another signaling pathway related to RGS4 involves the regulation of the immune response. RGS4 is expressed in various immune cells, including T cells and B cells, and has been shown to modulate immune cell activation and cytokine production. RGS4 acts as a negative regulator of T cell activation, and its expression is upregulated in response to T cell activation[6].
Implications of RGS protein dysregulation in disease:
The Dysregulation of RGS proteins has been implicated in a range of diseases, including cardiovascular disease, pain, hypertension, and cancer. In cardiovascular disease, RGS proteins play a critical role in regulating blood pressure and vascular function. Relating to pain, RGS4 in pain regulation is a topic of increasing interest because it has been identified as a key player in the modulation of nociception[7]. In hypertension, dysregulation of RGS proteins has been shown to contribute to the pathogenesis of the disease. While in cancer, RGS proteins are involved in regulating cell proliferation and survival[8].
In conclusion, RGS proteins are essential modulators for the GPCR signaling mediated by G proteins, which play a crucial role in regulating a range of physiological processes. The dysregulation of these proteins has been implicated in a range of diseases, and understanding the mechanisms of these complex molecules is crucial for developing effective therapies.
1. Tesmer, J.J., et al., Structure of RGS4 bound to AlF4--activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. Cell, 1997. 89(2): p. 251-61.
2. Senese, N.B., et al., Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management. Front Mol Neurosci, 2020. 13: p. 5.
3. Hollinger, S. and J.R. Hepler, Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. Pharmacol Rev, 2002. 54(3): p. 527-59.
4. Wang, Q., L.Y. Liu-Chen, and J.R. Traynor, Differential modulation of mu- and delta-opioid receptor agonists by endogenous RGS4 protein in SH-SY5Y cells. J Biol Chem, 2009. 284(27): p. 18357-67.
5. Zhuang, Y., et al., Structural insights into the human D1 and D2 dopamine receptor signaling complexes. Cell, 2021. 184(4): p. 931-942.e18.
6. Wang, D., The essential role of G protein-coupled receptor (GPCR) signaling in regulating T cell immunity. Immunopharmacol Immunotoxicol, 2018. 40(3): p. 187-192.
7. Avrampou, K., et al., RGS4 Maintains Chronic Pain Symptoms in Rodent Models. J Neurosci, 2019. 39(42): p. 8291-8304.
8. Hu, Y., et al., Identification of a five-gene signature of the RGS gene family with prognostic value in ovarian cancer. Genomics, 2021. 113(4): p. 2134-2144.