Voltage-gated calcium channel α₂δ-1 subunit is involved in the regulation of glucose-stimulated GLP-1 secretion in mice

Glucagon-like peptide-1 (GLP-1) is an incretin produced by enteroendocrine preproglucagon (PPG)-expressing cells in response to nutrient ingestion that potentiates insulin secretion. The voltage-gated Ca²⁺ channel has been reported previously to be involved in glucose-stimulated GLP-1 secretion; in this study, we show that PPG-cells in upper and lower small intestine substantially express the voltage-gated Ca²⁺ channel α₂δ-1 subunit (Ca_Vα₂δ-1). In vitro experiments using NCI-H716 cells demonstrate that inhibition of Ca_Vα₂δ-1 by gabapentin (GBP), an inhibitory ligand of the α₂δ subunit, attenuates glucose-stimulated intracellular calcium elevation and reduces GLP-1 secretion. In addition, systemic administration of gabapentin significantly reduces glucose-stimulated GLP-1 secretion without affecting blood glucose levels in wild-type mice. Furthermore, knockout mice of intestine-specific <i>Cacna2d1</i>, a gene encoding Ca_Vα₂δ-1, exhibit reduced GLP-1 secretion in response to oral glucose administration regardless of sex. These results demonstrate that Ca_Vα₂δ-1 expressed in PPG-cells plays an important role in glucose-stimulated GLP-1 secretion and represents a potential target in the treatment of diabetes and obesity.<b>NEW & NOTEWORTHY</b> In this study, we establish high expression of the voltage-gated Ca²⁺ channel α₂δ-1 subunit (Ca_Vα₂δ-1) subunit in enteroendocrine glucagon-like peptide-1 (GLP-1) producing cells and elucidate its role in GLP-1 secretion, providing a more detailed understanding of the mechanism of GLP-1 secretion.