G Proteins


Cells respond to many hormones, neurotransmitters, bioactive peptides and sensory molecules through G protein signalling. The process begins with the binding of the signalling molecule to the extracellular face of a G‐protein‐coupled receptor (GPCR) that initiates binding of the G protein heterotrimer on the intracellular side of the receptor. This interaction causes exchange of GDP for GTP on the G protein α subunit, triggering a conformational change that dissociates the Gα‐GTP from Gβγ. These G protein subcomplexes then interact with effector enzymes and ion channels and elicit a cellular response to the signal. GPCRs constitute the largest class of transmembrane receptors, with 800 genes in the human genome. Consequently, G protein signalling contributes to almost all aspects of human physiology, and GPCRs are the single most common class of drug targets.

Key Concepts

  • G protein signalling contributes to almost all aspects of human physiology, including sensory perception, neuronal transmission and hormone secretion.
  • Agonist binding to a G‐protein‐coupled receptor initiates an interaction with the G protein heterotrimer that triggers nucleotide exchange on the G protein α subunit (Gα).
  • The binding of GTP to Gα causes its dissociation from the receptor and the G protein βγ dimer (Gβγ), allowing Gα‐GTP and Gβγ to interact with effector enzymes and ion channels.
  • Effector enzymes and ion channels change the concentration of second messenger molecules or the membrane potential to elicit the cellular response to the agonist.
  • The rate of GTP hydrolysis by Gα, which determines the duration of the G protein signal, is controlled by GTPase‐accelerating proteins called regulators of G protein signalling.
  • To function, the G protein heterotrimer must be assembled from its individual subunits by molecular chaperones.

Keywords: heterotrimeric G protein; G‐protein‐coupled receptor; effector enzyme; ion channel; regulator of G protein signalling; molecular chaperone

Figure 1. Schematic illustration of the G‐protein cycle. See text for details. Structures are from the following PDB files: β2‐AR bound to Gs, 3SN6; Gi heterotrimer, 1GP2; Gαq bound to RGS8, 5DO9; Gαt, 1TAG; Gαs bound to adenylyl cyclase, 1AZS and Gβ1γ2‐GIRK, 5HE1.
Figure 2. (a) Phylogenetic tree of the Gα subunits. Alignments were done using ClustalX and trees were generated using FigTree. The scale bar represents evolutionary distance, a 0.05 fractional change in sequence. (b) Table of the Gα subunit families, examples of receptors that activate them, and their expression. (c) Schematics of effector activation by the different Gα families.
Figure 3. (a) Phylogenetic tree of the Gβ subunits. (b) Table of the Gβ subunits and their expression. (c) Phylogenetic tree of the Gγ subunits divided into subfamilies. (d) Table of the Gγ subunits and their expression.
Figure 4. (a) Structure of Gαt‐GTPγS (PDB 1TND). GTPγS is in magenta. (b) Aligned structures of Gαt‐GTPγS and Gαt‐GDP (PDB 1TND and 1TAG, respectively). Switch I, II and III regions are highlighted in orange and purple for the GTPγS‐ and GDP‐bound structures, respectively. GDP is shown in red. (c) Gβ1γ1 heterodimer (PDB 1TBG). Gβ1 is in blue and Gγ1 is in orange. (d) Gαtβ1γ1 heterotrimer (PDB 1GOT). Switch regions are highlighted in purple.
Figure 5. Schematic model for G protein biogenesis. See text for details.
Figure 6. (a) Structure of the Gs heterotrimer bound to β2‐AR (PDB 3SN6). The receptor is in red, Gα is in aqua, Gβ is in blue and Gγ is in orange. The α‐helical domain (AH) and the Ras domain are indicated. (b) The GTPγS‐bound form of Gαs (coral) (PDB 1AZT) aligned with the receptor‐bound Gαs (aqua), showing the changes in the structure when Gαs binds to the receptor. The receptor‐bound Gs was rotated ∼180° and Gβγ was removed to view the change in position of the α‐helical domain. (c) View of the changes in the α5 helix and the αN‐β1 loop in the GTP‐bound Gαs and the receptor‐bound Gαs. Colour scheme is the same as (b). (d) View of the changes in α1‐β1 and α5‐β6 loops.
Figure 7. (a) Structure of Gαs‐GTPγS bound to adenylyl cyclase (green) (PDB 1AZS). Switch regions are highlighted in purple. The α3 helix is highlighted in goldenrod. (b) Structure of Gαt‐GDP‐AlF4 bound to PDEγ (yellow) and RGS9 (pink) (PDB 1FQJ). (c) Gαq‐GDP‐AlF4 bound to PLCβ (salmon) (PDB 3OHM).
Figure 8. Changes in Gαt upon RGS9 binding. (a) RGS9 (pink) orients Thr 177 and Gln 200 on Gαt (aqua) to stabilise the transition state for GTP hydrolysis (PDB 1FQJ). Switch regions are in purple, GDP is in red, water is in blue, AlF4 is in yellow and Mg2+ is in green. (b) Comparison of RGS9‐bound Gαt‐GDP‐AlF4 with Gαt‐GTPγS (PDB 1TND) to show the changes in Thr 177 and Gln 200. RGS9‐bound Gαt‐GDP‐AlF4 is in purple and Gαt‐GTP is in orange.


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Further Reading

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Arshavsky VY and Burns ME (2012) Photoreceptor signaling: supporting vision across a wide range of light intensities. Journal of Biological Chemistry 287: 1620–1626.

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Lyon AM, Taylor VG and Tesmer JJ (2014) Strike a pose: Galphaq complexes at the membrane. Trends in Pharmacological Sciences 35: 23–30.

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Siderovski DP and Willard FS (2005) The GAPs, GEFs, and GDIs of heterotrimeric G‐protein alpha subunits. International Journal of Biological Sciences 1: 51–66.

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Zamponi GW and Currie KP (2013) Regulation of Ca(V)2 calcium channels by G protein coupled receptors. Biochimica et Biophysica Acta 1828: 1629–1643.

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Willardson, Barry M, and Tensmeyer, Nicole C(Aug 2017) G Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027195]