Review
Keynote review: Allosterism in membrane receptors

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Allosteric modulation of membrane receptors has been intensively studied in the past three decades and is now considered to be an important indirect mechanism for the control of receptor function. The allosteric site on the GABAA receptor is the target for the most widely prescribed sleep medicines, the benzodiazepines. Cinacalcet, an allosteric enhancer of the calcium-sensing receptor, is used to treat secondary hyperparathyroidism. Allosteric ligands might be especially valuable to control receptors for which the design of selective orthosteric agonists or antagonists has been elusive, such as muscarinic acetylcholine receptors.

Section snippets

GPCRs

GPCRs, which constitute the largest family of cell-surface receptors, are major targets of drugs currently in clinical use. The GPCRs display the characteristic motif of seven transmembrane helices (TMs) and thus are also referred to as 7TM receptors. The 7TM proteins account for ∼4% of the human genome. Mammalian GPCRs can be divided into three major subfamilies: class A, rhodopsin-like receptors; class B, secretin-like receptors; and class C, metabotropic glutamate-like and pheromone

Adenosine receptors

The A1 adenosine receptor (AR) was the first subtype in the AR family for which selective orthosteric and allosteric ligands were developed. The aminobenzoylthiophene derivative 2-amino-4,5-dimethyl-3-thienyl-[3-trifluoromethylphenyl]methanone (PD81723; Figure 1) was the first allosteric enhancer in the GPCR field, as originally observed by Bruns and Fergus [27]. They found that PD81723 enhances the binding of agonist radioligand [3H]cyclohexyladenosine to A1 ARs and decreases the rate of

Class B GPCRs: secretin-like receptors

Class B GPCRs (also known as the secretin-like receptor family) are a family of peptide-binding receptors comprising 15 members which share little sequence homology with class A (rhodopsin-like) or class C (mGlu) GPCRs. Several class B GPCRs, including corticotropin-releasing factor (CRF), growth hormone-releasing hormone, glucagon, secretin, calcitonin and parathyroid hormone (PTH) receptors, are crucially involved in controlling numerous important physiological processes [21].

Unlike some of

Class C GPCRs: metabotropic glutamate-like receptors

Glutamate is the major excitatory transmitter in the brain and binds to both LGICs and a family of class C GPCRs known as metabotropic glutamate receptors (mGluRs). Unlike most class A and class B GPCRs, class C GPCRs contain three domains: the extracellular Venus flytrap domain (VFD), which contains the agonist-binding site, the cysteine-rich domain (CRD) and the heptahelical domain (HD) involved in G protein activation [11]. In addition, the carboxy-terminal tail can be unusually long - for

LGICs

LGICs are membrane receptors responsible for rapid synaptic transmission and modulation of cellular activity. These channels are proteins spanning the cell membrane and forming both the binding site for the natural ligand and the ion-conducting pore, which can be opened or closed upon ligand binding. Upon activation, ion channels open to enable ion flux across the cell membrane. The flux can cause depolarization or hyperpolarization, depending on the charge and concentration of the ions.

Tyrosine kinase receptors

Tyrosine kinases are classified as transmembrane tyrosine kinase receptors (or receptor tyrosine kinases) and intracellular nonreceptor tyrosine kinases. Tyrosine kinase receptors are transmembrane proteins with a ligand-binding extracellular domain and a catalytic intracellular kinase domain. Emerging targets for cancer therapy [134], tyrosine kinase receptors have a central role in cellular growth, differentiation and oncogenesis. The activation of tyrosine kinase receptors by growth factors

Concluding remarks

Increasing evidence suggests that GPCR dimerization is common to all three classes of GPCRs. Original models describing the activation of a GPCR, especially the class A GPCRs, is generally related to the conformational change within a monomer. In the case of a dimer, it can be speculated that an orthosteric agonist for one dimerized monomer could be a positive or negative allosteric modulator for another monomer. From this point of view, most, if not all, membrane receptors could be naturally

Acknowledgements

We thank the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases for support and Srikar Rao for textual editing.

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    Allosteric modulators could be especially valuable in controlling receptors for which the design of orthosteric agonists or antagonists has been elusive.

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    Zhan-Guo Gao Zhan-Guo Gao is a Staff Scientist in the Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, NIH. After studying medicine, he became interested in the mechanisms of action of G-protein-coupled receptors. Both his current field of research and his PhD thesis work at the Leiden-Amsterdam Centre for Drug Research in The Netherlands concern adenosine receptors. He has published extensively on allosteric modulation of adenosine receptors.

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    Kenneth A. Jacobson Kenneth Jacobson is Chief of the Molecular Recognition Section of the Laboratory of Bioorganic Chemistry, NIDDK, NIH. He is a medicinal chemist with a research focus on receptors for nucleosides and nucleotides. Jacobson completed his PhD studies at the University of California, San Diego, USA, in 1981 and subsequent postdoctoral work at the Weizmann Institute of Science, Rehovot, Israel. He recently served as Chair of the Medicinal Chemistry Division of the American Chemical Society. He is a ‘highly cited researcher’ in Pharmacology and Toxicology (Institute for Scientific Information) and received the first Giuliana Fassina Award from the Purine Club in 1996, as well as the Hillebrand Prize of the Chemical Society of Washington in 2003 for ‘outstanding research contributions in the medicinal chemistry of G-protein-coupled receptors’.

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