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      GHS-R1a constitutive activity and its physiological relevance

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          Abundant evidences have shown that ghrelin, by its binding to GHS-R1a, plays an important role for fundamental physiological functions. Increasing attention is given to the GHS-R1a unusually high constitutive activity and its contribution to downstream signaling and physiological processes. Here, we review recent lines of evidences showing that the interaction between ligand-binding pocket TM domains and the ECL2 could be partially responsible for this high constitutive activity. Interestingly, GHSR-1a constitutive activity activates in turn the downstream PLC, PKC, and CRE signaling pathways and this activation is reversed by the inverse agonist [D-Arg 1, D-Phe 5, D-Trp 7,9, Leu 11]-substance P (MSP). Noteworthy, GHSR-1a exhibits a C-terminal-dependent constitutive internalization. Non-sense GHS-R1a mutation (Ala204Glu), first discovered in Moroccan patients, supports the role of GHSR-1a constitutive activity in physiological impairments. Ala204Glu-point mutation, altering exclusively the GHSR-1a constitutive activity, was associated with familial short stature syndrome. Altogether, these findings suggest that GHS-R1a constitutive activity could contribute to GH secretion or body weight regulation. Consequently, future research on basic and clinical applications of GHS-R1a inverse agonists will be challenging and potentially rewarding.

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          Most cited references 62

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          A receptor in pituitary and hypothalamus that functions in growth hormone release.

          Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.
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            Molecular mechanism of β-arrestin-biased agonism at seven-transmembrane receptors.

            The concept of biased agonism has recently come to the fore with the realization that seven-transmembrane receptors (7TMRs, also known as G protein-coupled receptors, or GPCRs) activate complex signaling networks and can adopt multiple active conformations upon agonist binding. As a consequence, the "efficacy" of receptors, which was classically considered linear, is now recognized as pluridimensional. Biased agonists selectively stabilize only a subset of receptor conformations induced by the natural "unbiased" ligand, thus preferentially activating certain signaling mechanisms. Such agonists thus reveal the intriguing possibility that one can direct cellular signaling with unprecedented precision and specificity and support the notion that biased agonists may identify new classes of therapeutic agents that have fewer side effects. This review focuses on one particular class of biased ligands that has the ability to alter the balance between G protein-dependent and β-arrestin-dependent signal transduction.
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              Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling.

              β-Arrestins, originally discovered to desensitize activated seven transmembrane receptors (7TMRs; also known as G-protein-coupled receptors, GPCRs), are now well established mediators of receptor endocytosis, ubiquitylation and G protein-independent signaling. Recent global analyses of β-arrestin interactions and β-arrestin-dependent phosphorylation events have uncovered several previously unanticipated roles of β-arrestins in a range of cellular signaling events. These findings strongly suggest that the functional roles of β-arrestins are much broader than currently understood. Biophysical studies aimed at understanding multiple active conformations of the 7TMRs and the β-arrestins have begun to unravel the mechanistic basis for the diverse functional capabilities of β-arrestins in cellular signaling. Copyright © 2011 Elsevier Ltd. All rights reserved.

                Author and article information

                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                29 May 2013
                : 7
                1CNRS, CRN2M UMR7286, Aix Marseille University Marseille, France
                2Molecular Biology Laboratory, Conception Hospital, AP-HM Marseille, France
                Author notes

                Edited by: María M. Malagón, University of Cordoba, Spain

                Reviewed by: Rhonda D. Kineman, University of Illinois at Chicago, USA; Jesus P. Camiña, Hospital Clínico Universitario de Santiago, Spain

                *Correspondence: Sylvie Thirion, Faculté de Médecine Nord, CRN2M - Neurobiology and Neurophysiological Research Center of Marseille, UMR CNRS 7286, Aix-Marseille University, Bd Pierre Dramard-CS 80011, 13344 Marseille Cedex 15, France e-mail: sylvie.thirion@ 123456univ-amu.fr

                This article was submitted to Frontiers in Neuroendocrine Science, a specialty of Frontiers in Neuroscience.

                Copyright © 2013 Mear, Enjalbert and Thirion.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 64, Pages: 7, Words: 5514
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                ghrelin receptor, gpcr, constitutive activity, signaling pathway, plc, β-arrestin


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