caa a22 4500 475846036 CHVBK 20180406123914.0 cr unu---uuuuu 170329e20000401xx s 000 0 eng 10.1007/PL00000725 doi (NATIONALLICENCE)springer-10.1007/PL00000725 The metabotropic GABA receptor: molecular insights and their functional consequences [Elektronische Daten] [S. Blein, E. Hawrot*, P. Barlow] Abstract.: Recent years have seen rapid and significant advances in our understanding of the G-protein-coupled γ-amino butyric acid, B-type (GABAB) receptor, which could be a therapeutic target in conditions as diverse as epilepsy and hypertension. This progress originated with the ground-breaking work of Bernhard Bettler's team at Novartis who cloned the DNA encoding a GABAB receptor in 1997. Currently, the receptor is thought to be an unusual, possibly unique, example of a heterodimer composed of homologous, seven-transmembrane-domain (7TMD) subunits (named GABAB R1 and GABAB R2), neither of which is fully functional when expressed alone. The large N-terminal domain of the GABAB R1 subunit projects extracellularly and contains a ligand binding site. The similarity of the amino acid sequence of this region to some bacterial periplasmic amino acid-binding proteins of known structure has enabled structural and functional modelling of the N-terminal domain, and the identification of residues whose substitution modulates agonist/antagonist binding affinities. The intracellular C-terminal domains of the R1 and R2 subunits appear to constitute an important means of contact between the two subunits. Alternative splice variants, a common and functionally important feature of 7TMD proteins, have been demonstrated for the R1 subunit. Notably GABAB R1a differs from GABAB R1b by the possession of an N-terminal extension containing two complement protein modules (also called SCRs, or sushi domains) of unknown function. The levels at which each of the respective variants is expressed are not equal to one another, with variations occurring over the course of development and throughout the central nervous system. It is not yet clear, however, whether one variant is predominantly presynaptically located and the other postsynaptically located. The existence of as yet unidentified splice variants, additional receptor subtypes and alternative quaternary composition has not been ruled out as a source of receptor heterogeneity. Birkhäuser Verlag Basel,, 2000 Key words. GABAB receptor nationallicence G-protein-coupled receptor nationallicence seven-transmembrane-domain receptor nationallicence short consensus repeats nationallicence sushi domains nationallicence drug target nationallicence Blein S. Edinburgh Centre for Protein Technology, Joseph Black Chemistry Building, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ (United Kingdom), GB aut Hawrot* E. Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence (Rhode Island 02912, USA), Fax +1 401 863 1595, e-mail: Edward_Hawrot@brown.edu, US aut Barlow P. Edinburgh Centre for Protein Technology, Joseph Black Chemistry Building, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ (United Kingdom), GB aut https://doi.org/10.1007/PL00000725 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/PL00000725 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Blein S. Edinburgh Centre for Protein Technology, Joseph Black Chemistry Building, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ (United Kingdom), GB aut NATIONALLICENCE 700 1- Hawrot* E. Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence (Rhode Island 02912, USA), Fax +1 401 863 1595, e-mail: Edward_Hawrot@brown.edu, US aut NATIONALLICENCE 700 1- Barlow P. Edinburgh Centre for Protein Technology, Joseph Black Chemistry Building, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ (United Kingdom), GB aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer