G Protein‐coupled Receptors

Joël Bockaert, University of Montpellier, France

Published online: March 2009

DOI: 10.1002/9780470015902.a0000118.pub2

Among membrane-bound receptors that recognize regulatory messages (hormones, neurotransmitters, photon, odours, etc.) the seven transmembrane receptors (7 TM) coupled to G proteins (G protein-coupled receptor, GPCRs) are the most numerous. They represent 3% of the total number of genes in human genome. They have similar three-dimensional (3D) structure but can be grouped into 8 classes that share few sequence similarities. GPCRs are targets for more than 50% of the drugs used in therapy.

Key concepts:

  • Cell–cell communication involved messages (hormone, neurotransmitter growth factors, odorant, etc.) and receptors, the majority of them being GPCRs.
  • GPCRs are 7 transmembrane receptors. They form homo- or heterodimers.
  • There are three main classes of GPCRs differing in they primary sequences.
  • The class 3 is the more original one having it binding site within an extra-cellular 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) virus use GPCRs such as those recognizing chemokines (CCR5, CXCR3) to enter specialized 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.

Keywords: signal transduction; receptors; G proteins; hormones; neurotransmitters

Figure 1. G protein-coupled receptor (GPCR) are homo- or heterodimers. GPCRs have seven transmembrane domains, three extracellular loops (e1, e2, e3) and three intracellular loops (i1, i2, i3). Heterotrimeric G proteins have three subunits: , and . are always associated. on one hand and on the other hand are covalently bound to lipids. These lipids allow the association of and 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, PAF (platelet-activating factor) and proteins such as TSH (thyroid-stimulating hormone), LH (luteinizing hormone), FSH (follicle-stimulating hormone). (b) Class 3 (or C) GPCRs. The dimmer can be a homodimer (e.g. the glutamate-metabotropic receptor: mGluRs) or a heterodimer (e.g. the GABAB receptors). The diversity of the ligandsis illustrated. It can be Ca2+, glutamate, GABA, sucrose and aspartame.
Figure 2. The cycle of activation of heterotrimeric G proteins, the role of G protein-coupled receptors (GPCRs) as guanyl nucleotide exchange factor (GEF) and the effectors. t, -transducin; -Gust, -gustducin; Rac and cdc42 are small G proteins; GIRK, G protein-regulated inward rectifying K+ channels; MAP kinases, mitogen-activated protein kinases; -AR kinase, -adrenergic receptor kinase.
Figure 3. Structure of 2-adrenergic receptor. The seven transmembrane helices plus the intracellular 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 helice in extracellular loop e2. Structure at 2.4 nm. Modified from Kobilka and Schertler (2008).
Figure 4. 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; TSH, thyroid-stimulating hormone.
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; Ptc, patched receptor.
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Related Sub-Topics:

Receptors for Neurotransmitters | Cell Membranes | Intracellular and Extracellular Signalling
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Article Title: G Protein‐coupled Receptors
 
How to Cite close
Bockaert, Joël(Mar 2009) G Protein‐coupled Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000118.pub2]