Glycine Receptor α2 Mediates Vasodilation via Endothelial eNOS Signaling

BACKGROUND: Endothelium-derived NO is an important vasodilator essential for maintaining vascular
homeostasis. However, how eNOS (endothelial nitric oxide synthase) is regulated in
hypertension conditions is not yet fully understood. In this study, we describe a
critical role of the GLRA2 (α2 subunit of glycine receptor) in modulating eNOS signaling
and blood pressure regulation. METHODS: Endothelial-specific Glra2-deficient mice and the adeno-associated viral-transfected mice were generated to
assess the role of GLRA2 in hypertension models. Endothelium-dependent relaxation
response and whole-cell patch clamp recording were determined. RESULTS: We first demonstrated selective expression of GLRA2 in arterial endothelial cells.
Activation of GLRA2 by its ligand, glycine, effectively counteracts hypertension in
a GLRA2-dependent manner. Our patient study indicated a negative correlation between
plasma levels of glycine and blood pressure. Furthermore, we showed that endothelial
GLRA2 regulates vasodilation by promoting NO production, rather than functioning solely
as a chloride channel. Mechanistically, GLRA2 facilitates the phosphorylation of glycogen
synthase kinase-3β at Ser9 (serine 9), which activates the AKT (protein kinase B)/eNOS
signaling pathway in the endothelium, leading to increased NO release. CONCLUSIONS: This study discovers that a novel endothelial GLRA2 pathway holds significant potential
for developing new strategies to control hypertension. Graphical Abstract

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