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GPCR in G Protein Signaling

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GPCR in G Protein Signaling

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GPCR in G Protein Signaling Background

GPCRs are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. The extracellular parts of the receptor can be glycosylated. These extracellular loops also contain two highly conserved cysteine residues that form disulfide bonds to stabilize the receptor structure. Some seven-transmembrane helix proteins that resemble GPCRs may contain ion channels, within their protein.

Signaling

If a receptor in an active state encounters a G protein, it may activate it. Some evidence suggests that receptors and G proteins are actually pre-coupled. For example, binding of G proteins to receptors affects the receptor's affinity for ligands. Activated G proteins are bound to GTP. Further signal transduction depends on the type of G protein. The enzyme adenylate cyclase is an example of a cellular protein that can be regulated by a G protein, in this case the G protein Gs (Figure 1). Adenylate cyclase activity is activated when it binds to a subunit of the activated G protein. Activation of adenylate cyclase ends when the G protein returns to the GDP-bound state. Adenylate cyclases may also be activated or inhibited in other ways, which can modify the activity of these enzymes in an additive or synergistic fashion along with the G proteins. The signaling pathways activated through a GPCR are limited by the primary sequence and tertiary structure of the GPCR itself but ultimately determined by the particular conformation stabilized by a particular ligand, as well as the availability of transducer molecules. Currently, GPCRs are considered to utilize two primary types of transducers: G-proteins and β-arrestins. Because β-arr's have high affinity only to the phosphorylated form of most GPCRs, the majority of signaling is ultimately dependent upon G-protein activation. However, the possibility for interaction does allow for G-protein-independent signaling to occur.

Structure of G protein Gs, protein was present as ribbon.Figure 1. Structure of G protein Gs, protein was present as ribbon.

G-protein-dependent signaling

There are three main G-protein-mediated signaling pathways, mediated by four sub-classes of G-proteins distinguished from each other by sequence homology. Each sub-class of G-protein consists of multiple proteins, each the product of multiple genes or splice variations that may imbue them with differences ranging from subtle to distinct with regard to signaling properties, but in general they appear reasonably grouped into four classes. Because the signal transducing properties of the various possible βγ combinations do not appear to radically differ from one another, these classes are defined according to the isoform of their α-subunit. While most GPCRs are capable of activating more than one Gα-subtype, they also show a preference for one subtype over another. When the subtype activated depends on the ligand that is bound to the GPCR, this is called functional selectivity (also known as agonist-directed trafficking, or conformation-specific agonism). However, the binding of any single particular agonist may also initiate activation of multiple different G-proteins, as it may be capable of stabilizing more than one conformation of the GPCR's GEF domain, even over the course of a single interaction. In addition, a conformation that preferably activates one isoform (Figure 2) of Gα may activate another if the preferred is less available. Furthermore, feedback pathways may result in receptor modifications that alter the G-protein preference. Regardless of these various nuances, the GPCR's preferred coupling partner is usually defined according to the G-protein most obviously activated by the endogenous ligand under most physiological or experimental conditions.

Protein A, B and C are isoforms encoded from the same gene through alternative splicingFigure 2 Protein A, B and C are isoforms encoded from the same gene through alternative splicing

G-protein-independent signaling

Although they are classically thought of working only together, GPCRs may signal through G-protein-independent mechanisms, and heterotrimeric G-proteins may play functional roles independent of GPCRs. GPCRs may signal independently through many proteins already mentioned for their roles in G-protein-dependent signaling such as β-arrs, GRKs, and Srcs. Such signaling has been shown to be physiologically relevant, for example, β-arrestin signaling mediated by the chemokine receptor CXCR3 was necessary for full efficacy chemotaxis of activated T cells. In addition, further scaffolding proteins involved in subcellular localization of GPCRs may also act as signal transducers. Most often the effector is a member of the MAPK family.

GPCR-independent signaling by heterotrimeric G-proteins

Although it is a relatively immature area of research, it appears that heterotrimeric G-proteins may also take part in non-GPCR signaling. There is evidence for roles as signal transducers in nearly all other types of receptor-mediated signaling, including integrins, receptor tyrosine kinases (RTKs) (Figure 3), cytokine receptors (JAK/STATs), as well as modulation of various other "accessory" proteins such as GEFs, guanine-nucleotide dissociation inhibitors (GDIs) and protein phosphatases. There may even be specific proteins of these classes whose primary function is as part of GPCR-independent pathways, termed activators of G-protein signaling (AGS). Both the ubiquity of these interactions and the importance of Gα vs. Gβγ subunits to these processes are still unclear.

Receptor protein tyrosine kinaseFigure 3. Receptor protein tyrosine kinase

References:

1. Qin K.; et al. nactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers. Nature Chemical Biology. 2011,7(10):740-747.

2. Wettschureck N.; Offermanns S. Mammalian G proteins and their cell type specific functions. Physiological Reviews. 2005,85 (4):1159–204.

3. Smith, Jeffrey S.; et al. Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation. Science Signaling.2018,11 (555): eaaq1075.

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