GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells

Abstract

Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating the ionotropic GABAA receptors on cerebrovascular endothelial cells, whereas the endothelial role of the metabotropic GABAB receptors is still unknown. Preliminary evidence showed that GABAA receptor stimulation can induce an increase in endothelial Ca2+ levels, but the underlying signaling pathway remains to be fully unraveled. In the present investigation, we found that GABA evoked a biphasic elevation in [Ca2+]i that was initiated by inositol-1,4,5-trisphosphate- and nicotinic acid adenine dinucleotide phosphate-dependent Ca2+ release from neutral and acidic Ca2+ stores, respectively, and sustained by store-operated Ca2+ entry. GABAA and GABAB receptors were both required to trigger the endothelial Ca2+ response. Unexpectedly, we found that the GABAA receptors signal in a flux-independent manner via the metabotropic GABAB receptors. Likewise, the full Ca2+ response to GABAB receptors requires functional GABAA receptors. This study, therefore, sheds novel light on the molecular mechanisms by which GABA controls endothelial signaling at the neurovascular unit.

Identification of Differentially Expressed miRNAs in Porcine Adipose Tissues and Evaluation of Their Effects on Feed Efficiency

“…Suppression of CLIC4 , the DEGs predicted as miR-122-5p, miR-155-5p, miR-196a and miR-9 targets, can significantly enhanced Ca(2+) release [ 101 ]. GABRE , the DEGs predicted as miR-122-5p, are involved in GABA signaling and mediate Ca 2+ signals [ 102 ]. It has been reported that ATP synthesis is associated with FE [ 103 ]; the genes OAS1 , MET , RHOBTB3 , HSPA4L , KIF20A , MST1R and MKI67 are related to ATP binding and there were DEGs predicted as DEM targets.…”

The Molecular Heterogeneity of Store-Operated Ca2+ Entry in Vascular Endothelial Cells: The Different roles of Orai1 and TRPC1/TRPC4 Channels in the Transition from Ca2+-Selective to Non-Selective Cation Currents

“…Recent findings suggest that Orai1 mediates endothelium-dependent NO production also at the neurovascular unit, where NO is crucial to increasing cerebral blood flow in response to neuronal activity [ 4 , 163 , 164 ]. The pharmacological blockade of Orai1 inhibited NO release induced in human cerebrovascular endothelial cells by multiple neurotransmitters, such as glutamate [ 165 , 166 ], GABA [ 167 , 168 ], and acetylcholine [ 62 ], and neuromodulators, including histamine [ 169 ] and arachidonic acid [ 170 ]. Interestingly, Orai2 is the only isoform expressed in mouse cerebrovascular endothelial cells [ 21 ], which is consistent with the crucial role played by Orai2 in neuronal SOCE in mice [ 74 ].…”