The N-Terminal Domain of γ-Aminobutyric AcidBReceptors Is Sufficient to Specify Agonist and Antagonist Binding

  1. Barbara Malitschek1,
  2. Claude Schweizer1,
  3. Miranda Keir1,2,
  4. Jakob Heid1,2,
  5. Wolfgang Froestl1,
  6. Johannes Mosbacher1,
  7. Rainer Kuhn1,
  8. Jeremy Henley,
  9. Cécile Joly3,
  10. Jean-Phillippe Pin3,
  11. Klemens Kaupmann1 and
  12. Bernhard Bettler1
  1. 1Novartis Pharma AG, Nervous System Research, Basel, Switzerland (B.M., C.S., M.K., J.H., W.F., J.M., R.K., K.K., B.B.); 2Bristol University, Department of Anatomy, Medical School, Bristol, United Kingdom (M.K., J.H.); and 3Centre National de la Recherche Scientifique, Mécanismes Moléculaires des Communications Cellulaires, Montpellier, France (C.J., J.-P.P.)

    Abstract

    The recently identified γ-aminobutyric acid type B receptors (GABABRs) share low sequence similarity with the metabotropic glutamate (mGlu) receptors. Like the mGlu receptors, the N-terminal extracellular domain (NTED) of GABABRs is proposed to be related to bacterial periplasmic binding proteins (PBPs). However, in contrast to the mGlu receptors, the GABABRs lack a cysteine-rich region that links the PBP-like domain to the first transmembrane domain. This cysteine-rich region is necessary for the PBP-like domain of mGlu receptors to bind glutamate. To delimit the ligand-binding domain of GABABRs, we constructed a series of chimeric GABABR1/mGluR1 and truncated GABABR1 receptor mutants. We provide evidence that despite the lack of a cysteine-rich region, the NTED of GABABRs contains all of the structural information that is necessary and sufficient for ligand binding. Moreover, a soluble protein corresponding to the NTED of GABABRs reproduces the binding pharmacology of wild-type receptors. This demonstrates that the ligand-binding domain of the GABABRs can correctly fold when dissociated from the transmembrane domains.

    Footnotes

    • Send reprint requests to: Dr. Bernhard Bettler, Novartis Pharma AG, K-125.6.08, Nervous System Research, CH-4002 Basel, Switzerland. E-mail:bernhard.bettler{at}pharma.novartis.com

    • Abbreviations:
      GABA
      γ-aminobutyric acid
      GABABR
      γ-aminobutyric acidB receptor
      R1a
      γ-aminobutyric acidB receptor 1a
      R1b
      γ-aminobutyric acidB receptor 1b
      R2
      γ-aminobutyric acidBreceptor 2
      mGlu
      metabotropic glutamate
      CaS
      calcium sensing
      PCR
      polymerase chain reaction
      PAGE
      polyacrylamide gel electrophoresis
      Ab
      antibody
      TMD
      transmembrane domain
      NTED
      N-terminal extracellular domain
      PBP
      periplasmic binding proteins
      WT
      wild-type
      • Received April 1, 1999.
      • Accepted May 7, 1999.
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    1. Molecular Pharmacology August 1, 1999 vol. 56 no. 2 448-454
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