G Protein‐Coupled Receptors


Among membrane‐bound receptors that recognise regulatory messages (hormones, neurotransmitters, photon, odours, etc.), the seven transmembrane receptors coupled to G proteins (G protein‐coupled receptors, GPCRs) are the most numerous. They represent 3% of the total number of genes in human genome. Following activation by those messages, GPCRs activate one or several heterotrimeric G proteins (α, β and γ subunits) by stimulating the guanosine diphosphate/guanosine triphosphate (GTP) exchange on the nucleotide binding site. The GTP form of the subunits activate effectors such as enzymes (e.g. the adenylyl cyclase) or channels. GPCRs can also trigger G protein‐independent signalling. GPCRs are targets for more than 30% of the drugs used in human therapy. Progress has been made recently on the structure and activation of GPCRs, thanks to the crystallisation of more than 60 GPCRs bound to agonists, antagonists and inverse‐agonists as well as a cocrystallisation between β2‐adrenergic receptors and its associated G protein.

Key Concepts:

  • Cell–cell communication involved messages (hormone, neurotransmitter growth factors, odorant, etc.) and receptors, the majority of them being GPCRs.

  • GPCRs are seven transmembrane receptors. They form homo‐ or heterodimers.

  • There are three main classes of GPCRs differing in their primary sequences.

  • The class 3 is the more original one having its binding site within an extracellular structure called ‘Venus fly trap’.

  • During evolution, mutations have tinkered the GPCR structure in order to allow recognition of ligands as diverse as photon, odorant, sugar, proteins, etc.

  • Virus, like human immunodeficiency virus (HIV), uses GPCRs such as those recognising chemokines (CCR5, CXCR3) to enter specialised cells such as macrophages or lymphocytes.

  • GPCRs are allosteric molecules and drugs can be developed enhancing or silencing the effect of the natural ligand without having any effect by themselves.

  • Mutations of GPCR are responsible of pathologies. These mutations can render the receptor constitutively active or inactive.

  • Analysis of GPCR structures using crystallisation and nuclear magnetic resonance (NMR) indicates that many ‘active’ and ‘inactive’ conformations do exist for each GPCR. They are stabilised by chemically different agonists, inverse‐agonists or antagonists.

  • The fully ‘active conformation’ is only obtained when the GPCR occupied by an agonist is associated with a G‐protein.

Keywords: signal transduction; GPCRs; G proteins; hormones; neurotransmitters, vision, olfaction, taste

Figure 1.

GPCRs are homo‐ or heterodimers. GPCRs have seven TM domains, three extracellular loops (e1, e2, e3) and three intracellular loops (i1, i2, i3). Heterotrimeric G proteins have three subunits: α, β and γ. β are always associated. α on one hand and βγ on the other hand are covalently bound to lipids. These lipids allow the association of α and βγ with the membrane. The effectors are enzymes, channels, transporters, etc. (a) Class 1 (or A) GPCR. The diversity of ligands of GPCRs is illustrated: photons, odorants, small endogenous molecules such as amino acids, nucleotides, nucleosides, prostaglandins, platelet‐activating factor (PAF) and proteins such as thyroid‐stimulating hormone (TSH), luteinizing hormone (LH), follicle‐stimulating hormone (FSH). (b) Class 3 (or C) GPCRs. The dimmer can be a homodimer (e.g. the glutamate‐metabotropic receptors, mGluRs) or a heterodimer (e.g. the GABAB receptors). The diversity of the ligands is illustrated. It can be Ca2+, glutamate, GABA, sucrose and aspartame.

Figure 2.

The cycle of activation of heterotrimeric G proteins, the role of GPCRs as GEF and the effectors. αt, α‐transducin; α‐Gust, α‐gustducin; Rac and cdc42 are small G proteins; GIRK, G protein‐regulated inward rectifying K+ channels; MAP kinases, mitogen‐activated protein kinases and β‐AR kinase, β‐adrenergic receptor kinase.

Figure 3.

The three most important familles of GPCRs. CRF, corticotropin releasing hormone; FSH, follicle‐stimulating hormone; GnRH, gonadotropin releasing hormone; IL8, interleukin 8; LH, luteinizing hormone; PACAP, pituitary adenylate cyclase activating polypeptide; PAF‐acether, platelet‐activating factor; PTH, parathyroid hormone; VIP, vasoactive intestinal peptide and TSH, thyroid‐stimulating hormone.

Figure 4.

Structure of β2‐adrenergic receptor. The seven TM α helices plus the intracellular α helice eight (parallel to the membrane) are labelled with roman numerals. The proline‐induced kinks in TM VI and VII are clear. The i3 loop is not figured. Note the α helice in extracellular loop e2. Structure at 2.4 nm. Modified from Kobilka and Schertler ().

Figure 5.

A touch of eccentricity in structure or function of GPCRs. CCR5‐CXCR4, chemokine receptors; Ci, cubitus interruptus; Hh, hedgehog; NT, neurotransmitter; PAR, protease‐activated receptor and Ptc, patched receptor.



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How to Cite close
Bockaert, Joël(Apr 2014) G Protein‐Coupled Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000118.pub3]