Ca²⁺ activity at GABA_B 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 neighboring inhibitory synapses, their function is not fully understood. Here we show a previously undescribed function of GABA_BR exerted independent of GABA. In cerebellar Purkinje cells, interaction of GABA_BR with extracellular Ca²⁺ (Ca _o²⁺) leads to a constitutive increase in the glutamate sensitivity of metabotropic glutamate receptor 1 (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 GABA_BR can act as Ca_o²⁺- dependent cofactors to enhance neuronal metabotropic glutamate signaling.