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Seven-transmembrane receptors


Seven-transmembrane receptors, which constitute the largest, most ubiquitous and most versatile family of membrane receptors, are also the most common target of therapeutic drugs. Recent findings indicate that the classical models of G-protein coupling and activation of second-messenger-generating enzymes do not fully explain their remarkably diverse biological actions.

Key Points

  • Seven-transmembrane (7TM) receptors form the largest superfamily of cell-surface receptors. They respond to a wide range of stimulants including light, hormones, neurotransmitters, and odorants.

  • Activation of 7TM receptors leads to the release of GDP and the binding of GTP to the a subunit of the heterotrimeric G protein. The a and bg dimers dissociate and both activate a number of effectors.

  • Several distinct mechanisms are involved in desensitizing responses mediated by 7TM receptors. These include RGS proteins, phosphorylation by second messenger dependent protein kinases and G-protein coupled receptor kinases, and the recruitment of β-arrestins.

  • In addition to roles in desensitizing 7TM receptors, β-arrestins are important for regulating receptor internalization, a process that, at least in some cases, requires β-arrestin ubiquitylation.

  • β-arrestins also serve as scaffolding proteins that facilitate non-classical 7 TM receptor signalling, including some instances of MAPK activation.

  • Recent advances in 7TM receptor biology include the pairing of orphan 7TM receptors with their cognate ligands, the interaction of 7TM receptors with novel partners, the realization that 7TM receptors signal, in part, via G protein independent mechanisms, and the crystallization of the first 7TM receptor, rhodopsin.

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Figure 1: Classical examples of seven-transmembrane (7TM)-receptor signalling.
Figure 2: Seven-transmembrane (7TM)-receptor trafficking.
Figure 3: β-arrestin scaffolding of mitogen-activated protein kinase (MAPK) cascades.
Figure 4: Heterodimerization of the GABAB receptor produces a functional receptor.


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Correspondence to Robert J. Lefkowitz.

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5-hydroxytryptamine receptor 1A

β2 adrenergic receptor

β-arrestin 1

β-arrestin 2




ARF-nucleotide-binding-site opener

angiotensin 1A receptor



















growth-hormone-releasing peptide















mouse double minute 2




prostacyclin receptor












V2 vasopressin receptor

vasoactive intestinal peptide

<i>Saccharomyces</i> genome database











A chemical substance with a distinct smell. Odorant receptors are a large group of 7TM receptors concentrated in the nasal epithelium that respond to a wide range of odours.


Guanine-nucleotide regulatory protein complexes composed of α and βγ subunits. They are responsible for transducing signals from 7TM receptors to effectors, including adenylyl cyclases and phospholipases.


Describing or relating to a regulatory cell that secretes an agonist into intercellular spaces in which it diffuses to a target cell other than the one that produces it.


Proteins that facilitate the replacement of GDP with GTP in the nucleotide-binding pocket of a GTP-binding protein.


The process by which segments of DNA are exchanged between two DNA duplexes that share high sequence similarity.


(GAPs) Proteins that inactivate GTP-binding proteins, such as heterotrimeric G proteins and Ras-family members, by increasing their rate of GTP hydrolysis.


Vasoactive peptides originally purified from bovine stomach extracts. These peptides interact with the recently de-orphanized 7TM receptor APJ.


Biogenic amines derived from amino-acid metabolism. Once thought of primarily as inactive metabolites, trace amines including tyramine and octopamine are now known to be important neuromodulators.


The main component of the coat that is associated with clathrin-coated vesicles, which are involved in membrane transport both in the endocytic and biosynthetic pathways.


Specialized rafts that contain the protein caveolin and form a flask-shaped, cholesterol-rich invagination of the plasma membrane. This might mediate the uptake of some extracellular materials and is probably involved in cell signalling.


A protein that augments cellular responses by recruiting other proteins to a complex. They usually contain several protein–protein interaction domains.


A member of a family of so-called 'clathrin adaptor proteins', which facilitate the early stages of endocytic vesicle formation through their ability to bind clathrin coats.


A GTPase that takes part in endocytosis. It seems to be involved in severing the connection between the nascent vesicle and the donor membrane.


Organelles that carry materials ingested by endocytosis and pass them to lysosomes for degradation or recycle them to the cell surface.


A 76-amino-acid protein that can be covalently attached to specific lysine residues in target proteins. This often forms multimeric polyubiquitin chains, which are thought to target the protein for destruction.


Protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.


An enzyme that activates the carboxy-terminal glycine of the small protein ubiquitin, or ubiquitin-like proteins, allowing them to form a high-energy bond to a specific cysteine residue of the E1.


An enzyme that accepts ubiquitin or a ubiquitin-like protein from an E1 and transfers it to the substrate, mostly using an E3 enzyme.


E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.


(ARF) A small GTPase that regulates the assembly of coats and vesicle budding.


Proteins that have specific binding sites and are therefore important in the assembly and function of larger molecular complexes.


(LPA) Any phosphatidic acid that is deacylated at positions 1 or 2.


Axial bundles of F-actin connecting focal adhesions.


Protein-interaction domains that often occur in scaffolding proteins and are named after the founding members of this protein family (Psd-95, discs-large and ZO-1).


These 7TM receptors are produced at high levels in the nervous system. They are important for modulating pain responses. Many analgesic drugs target these receptors, including codeine, morphine and heroin.

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Pierce, K., Premont, R. & Lefkowitz, R. Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3, 639–650 (2002).

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