Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors

  title={Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors},
  author={Klemens Kaupmann and K Huggel and Jakob Heid and Peter Josef Flor and Serge François Bischoff and Stuart J Dr Mickel and Gary Mcmaster and Christof Angst and Helmut Bittiger and Wolfgang Froestl and Bernhard Bettler},
GABA (γ-amino-butyric acid), the principal inhibitory neurotransmitter in the brain, signals through ionotropic (GABAA/GABAC) and metabotropic (GABAB) receptor systems. Here we report the cloning of GABAB receptors. Photoaffinity labelling experiments suggest that the cloned receptors correspond to two highly conserved GABAB receptor forms present in the vertebrate nervous system. The cloned receptors negatively couple to adenylyl cyclase and show sequence similarity to the metabotropic… 

Characteristics of GABAB Receptor Mutant Mice

The phenotypes of GABAB knockout mice are reviewed and how genetic experiments have contributed to the current understanding of the GABAB receptor system are discussed.

Processing of GABABR1 in Heterologous Expression Systems

The cellular localization of a GFP-tagged GABABR1 and the coupling of the cloned receptor to potassium channels are analyzed and may in retrospect explain why functional expression cloning of GABA BR1 was unsuccessful.

γ-Aminobutyric Acid (GABA) Receptors

γ-Aminobutyric acid (GABA) is the most widely distributed inhibitory neurotransmitter in the central nervous system of adult vertebrates. Virtually all neurons are sensitive to GABA through its

The GABAB Receptor

Cloning of the GABAB(l) cDNA was a major milestone in the field as it paved the way for studies on the structure, function, and pharmacology of GABAB receptors at the molecular level.

Native GABAB receptors are heteromultimers with a family of auxiliary subunits

It is shown by functional proteomics that GABAB receptors in the brain are high-molecular-mass complexes of GABAB1, GABAB2 and members of a subfamily of the KCTD (potassium channel tetramerization domain-containing) proteins, established as auxiliary subunits of GABAb receptors that determine the pharmacology and kinetics of the receptor response.

Intracellular Retention of Recombinant GABABReceptors*

It is reported that recombinant GABAB receptors fail to reach the cell surface when expressed in heterologous systems and are retained in the endoplasmic reticulum when introduced into COS cells and proved that they fail to activate in superior cervical ganglion neurons.

The Unusual Functioning of the GABAB-Receptor Heterodimer

The focus will be on nonclassical aspects of GABAB receptor phosphorylation, desensitization, downregulation, signaling, and association with a variety of protein partners.

The diversity of GABAA receptors

The pharmacology of putative receptor isoforms is summarized and the characteristics of functional channels are emphasized to further the understanding of GABA-related disorders and of the complex interaction of excitatory and inhibitory mechanisms in neuronal processing.

Heterodimerization is required for the formation of a functional GABAB receptor

The cloning of a complementary DNA encoding a new subtype of the GABAB receptor (GABABR2), which is identified by mining expressed-sequence-tag databases, indicates that, in vivo, functional brain GABAB receptors may be heterodimers composed of GABABR1 and GABABR2.



Functional domains of GABAA receptors.

Functional evidence for multiple gamma-aminobutyric acidB receptor subtypes in the rat cerebral cortex.

The aim of this work was the identification of pharmacologically distinct subtypes of gamma-aminobutyric acidB (GABAB) receptors in the central nervous system by choosing as models the GABAB receptors mediating inhibition of release of endogenous GABA; 2) endogenous glutamate; and 3) somatostatin-like immunoreactivity (SRIF-LI).

gamma-aminobutyric acid B receptors are negatively coupled to adenylate cyclase in brain, and in the cerebellum these receptors may be associated with granule cells.

The GABAB receptor is negatively coupled to adenylate cyclase in various brain areas, and, in the cerebellum, data suggest a granule cell localization of this activity.

GABAB receptors as targets for drug action.

The background to GABAB receptor research is reviewed and the future of drugs targetting the receptor is considered, which indicates the therapeutical potential for antagonists of the receptor has yet to be examined.

Inhibition of GABAB Receptor Binding by Guanyl Nucleotides

GTP and GDP decreased the saturable binding of GABAB to GABAB but not GABAA receptors whereas GMP displayed negligible activity, and the inhibition of ligand binding was the result of a diminished receptor affinity with no change in receptor number.