title: Variants of G protein-coupled receptors: a reappraisal of their role in receptor regulation.
abstract: Truncated or shorter forms of G protein-coupled receptors (GPCRs), originating by alternative splicing, have been considered physiologically irrelevant for a rather long time. Nevertheless, it is now recognized that alternative splicing variants of GPCRs greatly increase the total number of receptor isoforms and can regulate receptor trafficking and signalling. Furthermore, dimerization of these truncated variants with other receptors concurs to expand receptor diversity. Highly truncated variants of GPCRs, typically, are retained in the endoplasmic reticulum (ER) and by heteromerization prevent the wild-type receptor to reach the plasma membrane, exerting a dominant-negative effect on its function. This can be responsible for some pathological conditions but in some other cases, it can offer protection from a disease because the expression of the receptor, that is necessary for binding an infectious agent, is attenuated. Here, we propose a possible new mechanism of creation of truncated GPCR variants through an internal ribosome entry site (IRES), a nucleotide sequence that allows cap independent translation of proteins by recruiting the ribosome in proximity of an internal initiation codon. We suggest that an IRES, situated in the third cytoplasmic loop, could be responsible for the translation of the last two transmembrane (TM) regions of the muscarinic M2receptor. IRES driven expression of this C-terminal part of the muscarinic M2receptor could represent a novel and additional mechanism of receptor regulation.
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy roberto.maggio@univaq.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Maggio
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Fasciani
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, U.S.A.
authors.forename: Mario
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Di Gregorio
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Pietrantoni
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Puca
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Flati
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Scarselli
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D006801:Humans; D000067556:Internal Ribosome Entry Sites; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000067556:Internal Ribosome Entry Sites; D043562:Receptors, G-Protein-Coupled
keywords: G protein-coupled receptor; dimerization; internal ribosome entry site; muscarinic receptor; receptor fragment; slice variant