GABA A and GABA B Receptors Mediate GABA-Induced Intracellular Ca 2+ Signals in Human Brain Microvascular Endothelial Cells.

Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating the ionotropic GABA A receptors on cerebrovascular endothelial cells, whereas the endothelial role of the metabotropic GABA B receptors is still unknown. Preliminary evidence showed that GABA A receptor stimulation can induce an increase in endothelial Ca 2+ levels, but the underlying signaling pathway remains to be fully unraveled. In the present investigation, we found that GABA evoked a biphasic elevation in [Ca 2+ ] i that was initiated by inositol-1,4,5-trisphosphate- and nicotinic acid adenine dinucleotide phosphate-dependent Ca 2+ release from neutral and acidic Ca 2+ stores, respectively, and sustained by store-operated Ca 2+ entry. GABA A and GABA B receptors were both required to trigger the endothelial Ca 2+ response. Unexpectedly, we found that the GABA A receptors signal in a flux-independent manner via the metabotropic GABA B receptors. Likewise, the full Ca 2+ response to GABA B receptors requires functional GABA A receptors. This study, therefore, sheds novel light on the molecular mechanisms by which GABA controls endothelial signaling at the neurovascular unit.