Ca2+ activity at GABAB receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16952-7. doi: 10.1073/pnas.0405387101. Epub 2004 Nov 18.


Type B gamma-aminobutyric acid receptor (GABABR) is a G protein-coupled receptor that regulates neurotransmitter release and neuronal excitability throughout the brain. In various neurons, GABABRs are concentrated at excitatory synapses. Although these receptors are assumed to respond to GABA spillover from neighboring inhibitory synapses, their function is not fully understood. Here we show a previously undescribed function of GABABR exerted independent of GABA. In cerebellar Purkinje cells, interaction of GABABR with extracellular Ca2+ (Ca(2+)o) leads to a constitutive increase in the glutamate sensitivity of metabotropic glutamate receptor 1 (mGluR1). mGluR1 sensitization is clearly mediated by GABABR because it is absent in GABABR1 subunit-knockout cells. However, the mGluR1 sensitization does not require G(i/o) proteins that mediate the GABABR's classical functions. Moreover, coimmunoprecipitation reveals complex formation between GABABR and mGluR1 in the cerebellum. These findings demonstrate that GABABR can act as Ca(2+)o-dependent cofactors to enhance neuronal metabotropic glutamate signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Calcium / metabolism*
  • DNA Primers
  • GABA-B Receptor Agonists
  • Glutamic Acid / metabolism*
  • Immunoprecipitation
  • Mice
  • Mice, Inbred C57BL
  • Receptors, GABA-B / metabolism*
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction*
  • gamma-Aminobutyric Acid / metabolism*


  • DNA Primers
  • GABA-B Receptor Agonists
  • Receptors, GABA-B
  • Receptors, Metabotropic Glutamate
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Calcium