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

Type B γ-aminobutyric acid receptor (GABA_BR) is a G protein-coupled receptor that regulates neurotransmitter release and neuronal excitability throughout the brain. In various neurons, GABA_BRs are concentrated at excitatory synapses. Although these receptors are assumed to respond to GABA spillover from neigh- boring 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, inter- action of GABABR with extracellular Ca²⁺ (Car) leads to a constitutive increase in the glutamate sensitivity of metabotropic glutamate receptor I (mGluR1). mGluR1 sensitization is clearly mediated by GABA_BR because it is absent in GABA_BR1 subunit- knockout cells. However, the mGluR1 sensitization does not require G_i/o proteins that mediate the GABA_BR's classical functions. Moreover, coimmunoprecipitation reveals complex formation between GABA_BR and mGluR1 in the cerebellum. These findings demonstrate that GABABR can act as Ca_o²⁺-dependent cofactors to enhance neuronal metabotropic glutamate signaling. [ABSTRACT FROM AUTHOR]