Journal ArticleDOI
Gabab-receptor subtypes assemble into functional heteromeric complexes
Klemens Kaupmann,Barbara Malitschek,Valerie Schuler,Jakob Heid,Wolfgang Froestl,Pascal Beck,Johannes Mosbacher,Serge Bischoff,Ákos Kulik,Ryuichi Shigemoto,Andreas Karschin,Bernhard Bettler +11 more
TLDR
A new GABAB receptor subtype is described, GABABR2, which does not bind available GABAB antagonists with measurable potency and exhibits a significant increase in agonist- and partial-agonist-binding potencies as compared with individual receptors.Abstract:
B-type receptors for the neurotransmitter GABA (gamma-aminobutyric acid) inhibit neuronal activity through G-protein-coupled second-messenger systems, which regulate the release of neurotransmitters and the activity of ion channels and adenylyl cyclase. Physiological and biochemical studies show that there are differences in drug efficiencies at different GABA(B) receptors, so it is expected that GABA(B)-receptor (GABA(B)R) subtypes exist. Two GABA(B)-receptor splice variants have been cloned (GABA(B)R1a and GABA(B)R1b), but native GABA(B) receptors and recombinant receptors showed unexplained differences in agonist-binding potencies. Moreover, the activation of presumed effector ion channels in heterologous cells expressing the recombinant receptors proved difficult. Here we describe a new GABA(B) receptor subtype, GABA(B)R2, which does not bind available GABA(B) antagonists with measurable potency. GABA(B)R1a, GABA(B)R1b and GABA(B)R2 alone do not activate Kir3-type potassium channels efficiently, but co-expression of these receptors yields a robust coupling to activation of Kir3 channels. We provide evidence for the assembly of heteromeric GABA(B) receptors in vivo and show that GABA(B)R2 and GABA(B)R1a/b proteins immunoprecipitate and localize together at dendritic spines. The heteromeric receptor complexes exhibit a significant increase in agonist- and partial-agonist-binding potencies as compared with individual receptors and probably represent the predominant native GABA(B) receptor. Heteromeric assembly among G-protein-coupled receptors has not, to our knowledge, been described before.read more
Citations
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Molecular tinkering of G protein‐coupled receptors: an evolutionary success
Joël Bockaert,Jean-Philippe Pin +1 more
TL;DR: Indirect studies have led to a useful model of a common ‘central core’, composed of seven transmembrane helical domains, and its structural modifications during activation of G protein‐coupled receptors.
Journal ArticleDOI
Human receptors for sweet and umami taste
TL;DR: It is shown that human T1R2/T1R3 recognizes diverse natural and synthetic sweeteners, and this response is enhanced by 5′-ribonucleotides, a hallmark of umami taste, which implicate the T1Rs inUmami taste and suggest that sweet and Umami taste receptors share a common subunit.
Journal ArticleDOI
Extracellular Calcium Sensing and Extracellular Calcium Signaling
Edward M. Brown,R. John MacLeod +1 more
TL;DR: The cloning of a G protein-coupled extracellular Ca(2+) (Ca(o)(2+))-sensing receptor (CaR) has elucidated the molecular basis for many of the previously recognized effects of Ca( o)(2+) on tissues that maintain systemic Ca(o](2+) homeostasis, especially parathyroid chief cells and several cells in the kidney.
Journal ArticleDOI
Uncovering Molecular Mechanisms Involved in Activation of G Protein-Coupled Receptors
TL;DR: The goal of the present review is to specifically address the physical changes linking agonist binding to receptor activation and subsequent transduction of the signal to the associated G protein on the cytoplasmic side of the membrane and to other putative signaling pathways.
Journal ArticleDOI
Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor
Naoki Kunishima,Yoshimi Shimada,Yuji Tsuji,Toshihiro Sato,Masaki Yamamoto,Takashi Kumasaka,Shigetada Nakanishi,Hisato Jingami,Kosuke Morikawa +8 more
TL;DR: Three different crystal structures of the extracellular ligand-binding region of mGluR1 are determined—in a complex with glutamate and in two unliganded forms, implying that glutamate binding stabilizes both the ‘active’ dimer and the ’closed’ protomer in dynamic equilibrium.
References
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TL;DR: A new method for identifying secretory signal sequences and for predicting the site of cleavage between a signal sequence and the mature exported protein is described.
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RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor.
Linda M. McLatchie,Neil J. Fraser,Martin J. Main,Alan Wise,Jason L. Brown,Nicola Thompson,Roberto Solari,Melanie G. Lee,Steven M. Foord +8 more
TL;DR: It is shown that a receptor with seven transmembrane domains, the calcitonin-receptor-like receptor (CRLR), can function as either a CGRP receptor or an adrenomedullin receptor, depending on which members of a new family of single-trans Membrane-domain proteins, which are called receptor-activity-modifying proteins or RAMPs, are expressed.
Journal ArticleDOI
Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors.
Klemens Kaupmann,Katharina Huggel,Jakob Heid,Peter J. Flor,Serge Bischoff,Stuart J. Mickel,Mcmaster Gary Kent,Christof Angst,Helmut Bittiger,Wolfgang Froestl,Bernhard Bettler +10 more
TL;DR: The cloning of GABAB receptors is reported and photoaffinity labelling experiments suggest that the cloned receptors correspond to two highly conserved GABAB receptor forms present in the vertebrate nervous system.
Journal ArticleDOI
G Protein-Coupled Inwardly Rectifying K+ Channels (GIRKs) Mediate Postsynaptic but Not Presynaptic Transmitter Actions in Hippocampal Neurons
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Journal ArticleDOI
The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins
Patrick J. O'Hara,Paul O. Sheppard,Henning Thøgersen,Domenick Venezia,Betty A. Haldeman,Vicki McGrane,Khaled M. Houamed,Christian Thomsen,Teresa Gilbert,Eileen R. Mulvihill +9 more
TL;DR: Sensitive sequence analysis techniques indicate that the metabotropic receptor extracellular domain is similar to bacterial periplasmic amino acid binding proteins, and a structural model built using the observed similarity predicts a ligand-binding site, and mutants with conservative amino acid substitutions at this site are shown to have reduced ligand affinity.
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Kenneth A. Jones,Beth E. Borowsky,Joe A. Tamm,Douglas A. Craig,Margaret M. Durkin,Meng Dai,Wen-Jeng Yao,Mary C. Johnson,Caryn A Gunwaldsen,Ling-Yan Huang,Cheng Tang,Quanrong Shen,John Salon,Kelley L. Morse,Thomas M. Laz,Kelli E. Smith,Dhanapalan Nagarathnam,Stewart A. Noble,Theresa Branchek,Christophe P. G. Gerald +19 more