GPCRs (also known as metabotropic or seven transmembrane spanning receptors) are the largest family of membrane proteins in the human genome. They are coupled to intracellular signaling pathways via a G protein, which is comprised of three subunits – α, ß and γ. It is the Gα subunit that forms a heterotrimeric complex with Gß and Gγ subunits and possess GTPase activity1.
GPCRs consist of a single polypeptide chain, and generally have a monomeric structure (although they may occasionally be dimeric) comprising of seven transmembrane helices. The N-terminal domain is extracellular whilst the C-terminus is located intracellularly.
There are three structurally different GPCR subtypes - type I bind small organic molecules in the transmembrane region of the receptor; type II bind peptide hormones and proteins to the extracellular sequences and type III have large extracellular domains and bind a variety of ligands including small amino acids and calcium.
How do GPCRs work?
- Agonist binds
- The receptor undergoes a conformational change
- The strong ionic interaction between transmembrane helices is disrupted
- Activation of G protein heterotrimer
- Downstream signaling pathways may be activated
- Dependent on the type of G protein activated
- Desensitization of signaling following arrestin binding leading to GPCR internalisation
- May have short or long-term effects 2, 3
At least one third of drugs that are currently available on the market target GPCRs.
Figure 1: Diagram summarising how GPCRs work.
Second messengers triggered by GPCR activation
The activation of a single G protein can lead to alterations in the production of hundreds or even thousands of intracellular second messenger molecules, with short or long-term effects 2, 3. Common targets include:
- Adenylyl cyclase – activated by GTPα bound subunit catalysing the synthesis of cAMP from ATP
- Phospholipase C – catalyses the synthesis of DAG and IP3
Types of GPCRs
- Biogenic amines – Dopamine, Histamine, Glutamate, mACh and serotonin
- Lipid immunomodulators – PG, prostanoids, PAF and LT
- Peptide hormones - CGRP, GnRH, FSH, oxytocin and cannabinoids
1. Kroeze WK et al. G-protein coupled receptors at a glance. J Cell Science 116: 4867-69 (2003). Read more (PubMed:14625380) »
2. Marinissen MJ and Gutkind JS. G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol. Sci 22: 368-76 (2001). Read more (PubMed:11431032) »
3. Neves SR et al. G protein pathways. Science. 296: 1636-1639 (2002). Read more (PubMed:12040175) »
GPCR technical resources