G protein coupled receptors as allosteric proteins and the role of allosteric modulators.
ABSTRACT Seven transmembrane receptors (7TMRs) are proteins that convey signals through changes in conformation. These conformations are stabilized by external molecules (i.e. agonists, antagonists, modulators) and act upon other bodies (termed 'guests') which can be other molecules in the extracellular space, or proteins along the plane of the membrane (receptor oligomerization) or signaling proteins in the cytosol (i.e. G protein, β-arrestin). These elements comprise allosteric systems and a great deal of 7TMR pharmacology can be considered in terms of allosteric behavior. Allosteric ligands acting on 7TMRs possess four unique behaviors that can be valuable therapeutically; (1) the ability to alter the interaction of very large proteins, (2) probe dependence, (3) saturable effect, and (4) induction of separate changes in affinity and efficacy of other ligands. Two of these behaviors (namely probe dependence for CCR5-based HIV-1 entry inhibitors and functional selectivity for biased agonism) will be highlighted with examples.
SourceAvailable from: Eugénie Goupil[Show abstract] [Hide abstract]
ABSTRACT: The angiotensin II (Ang II) type I (AT1R) and the prostaglandin F2α (PGF2α) F prostanoid (FP) receptors are both potent regulators of blood pressure. Physiological interplay between AT1R and FP has been described. Abdominal aortic ring contraction experiments revealed that PGF2α-dependent activation of FP potentiated Ang II-induced contraction whereas FP antagonists had the opposite effect. Similarly, PGF2α-mediated vasoconstriction was symmetrically regulated by co-treatment with AT1R agonist and antagonist. The underlying canonical Gαq signaling via production of inositol phosphates mediated by each receptor was also regulated by antagonists for the other receptor. However, binding to their respective agonists, regulation of receptor-mediated MAPK activation and VSMC growth were differentially or asymmetrically regulated depending on how each of the two receptors were occupied by either agonist or antagonist. Physical interactions between these receptors have never been reported and here we show that AT1R and FP form heterodimeric complexes in both HEK 293 and vascular smooth muscle cells (VSMC). These findings imply that formation of the AT1R/FP dimer creates a novel allosteric signaling unit that shows symmetrical and asymmetrical signaling behavior, depending on the outcome measured. AT1R/FP dimers may thus be important in the regulation of blood pressure.Journal of Biological Chemistry 12/2014; 290(5). DOI:10.1074/jbc.M114.631119 · 4.60 Impact Factor
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ABSTRACT: Self-organization of cell-surface receptors in structurally distinct domains in the plasma membrane is of vital importance for correct cellular signaling. However, this dynamic process is difficult to study in cells with sufficiently high temporal and spatial resolution. Herein, two quantitative high-resolution methods with single-molecule sensitivity are presented, i.e., fluorescence correlation spectroscopy (FCS) and pair-correlation photo-activated localization microscopy (pcPALM), which enable the non-destructive study of receptor diffusion and lateral organization at the nanoscale level. The methods are introduced and their application in studies of lateral organization of G protein-coupled receptors (GPCRs) is reviewed. Examples from studies on the lateral organization of opioid receptors are presented in order to illustrate the most recent advances in the field.Journal of the Serbian Chemical Society 01/2013; 78(11):1671-1688. DOI:10.2298/JSC130815102J · 0.89 Impact Factor
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ABSTRACT: Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.ACS Chemical Neuroscience 09/2014; DOI:10.1021/cn500153z · 4.21 Impact Factor