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The Journal of Neuroscience, February 15, 2001, 21(4):1189-1202
C-Terminal Interaction Is Essential for Surface Trafficking But Not for Heteromeric Assembly of GABAB Receptors
Adriana Pagano1, 2, Giorgio Rovelli1, Johannes Mosbacher1, Tania Lohmann1, 4, Beatrice Duthey3, Daniela Stauffer1, Dorothee Ristig1, Valerie Schuler1, Ingeborg Meigel1, Christina Lampert1, Thomas Stein1, Laurent Prézeau3, Jaroslav Blahos3, Jean-Philippe Pin3, Wolfgang Froestl1, Rainer Kuhn1, Jakob Heid1, Klemens Kaupmann1, and Bernhard Bettler1 1 Novartis Pharma AG, Therapeutic Area Nervous System, CH-4002 Basle, Switzerland, 2 Dipartimento di Scienze Chimiche, Università di Catania, 95125 Catania, Italy, 3 Mécanismes Moléculaires des Communications Cellulaires UPR 9023, Centre National de la Recherche Scientifique CCIPE, 34094 Montpellier Cedex 05, France, and 4 Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo-ICB/USP, 05508-900, São Paulo, Brazil
Assembly of fully functional GABAB receptors requires heteromerization of the GABAB(1) and GABAB(2) subunits. It is thought that GABAB(1) and GABAB(2) undergo coiled-coil dimerization in their cytoplasmic C termini and that assembly is necessary to overcome GABAB(1) retention in the endoplasmatic reticulum (ER). We investigated the mechanism underlying GABAB(1) trafficking to the cell surface. We identified a signal, RSRR, proximal to the coiled-coil domain of GABAB(1) that when deleted or mutagenized allows for surface delivery in the absence of GABAB(2). A similar motif, RXR, was recently shown to function as an ER retention/retrieval (ERR/R) signal in KATP channels, demonstrating that G-protein-coupled receptors (GPCRs) and ion channels use common mechanisms to control surface trafficking. A C-terminal fragment of GABAB(2) is able to mask the RSRR signal and to direct the GABAB(1) monomer to the cell surface, where it is functionally inert. This indicates that in the heteromer, GABAB(2) participates in coupling to the G-protein. Mutagenesis of the C-terminal coiled-coil domains in GABAB(1) and GABAB(2) supports the possibility that their interaction is involved in shielding the ERR/R signal. However, assembly of heteromeric GABAB receptors is possible in the absence of the C-terminal domains, indicating that coiled-coil interaction is not necessary for function. Rather than guaranteeing heterodimerization, as previously assumed, the coiled-coil structure appears to be important for export of the receptor complex from the secretory apparatus.
Key words: GABA-B receptor; G-protein; metabotropic; heterodimer; endoplasmatic reticulum; coiled-coil
-helices; leucine zippers
Copyright © 2001 Society for Neuroscience 0270-6474/01/2141189-14$05.00/0
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[Abstract]
