Upregulation of astrocytic mitochondrial functions via Korean red ginseng-induced CREB-BKα-HIF-1α axis through L-type Ca2+ channel subunits α1C and β4.

Abstract

Korean red ginseng extract (KRGE) enhances astrocytic functions through hypoxia-inducible factor-1α (HIF-1α). Astrocytic Ca²⁺ influx through L-type Ca²⁺ channels (LTCCs) facilitates neurovascular communication, while the large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channel mediates K⁺ efflux for vasodilation. However, the role of LTCC subunits in KRGE-mediated BKα and HIF-1α expression in astrocytes remains unclear. This study aimed to investigate the effects of KRGE on LTCC subunits, cytosolic Ca²⁺ influx, and BKα and HIF-1α induction in human astrocytes. The levels of BKα, LTCCs, and HIF-1α were analyzed in KRGE-treated mouse brain tissue using immunohistochemistry. Human astrocytes treated with an LTCC agonist exhibited increased BKα and HIF-1α protein levels. Similarly, KRGE increased the levels of LTCC subunits α1 C and β4, cytosolic Ca²⁺ influx, BKα, and HIF-1α. Moreover, knockdown of either α1 C or β4 attenuated KRGE-induced increases in Ca²⁺ influx and HIF-1α levels. Notably, their combined knockdown synergistically reduced KRGE-induced increases in BKα levels, mitochondrial mass, ATP production, and O₂ consumption. The corpus callosum astrocytes of KRGE-treated mice exhibited increased levels of α1 C and β4, BKα, HIF-1α, and cAMP-response element binding protein (CREB). Collectively, these findings suggest that KRGE induced astrocytic BKα and HIF-1α expression via LTCC-mediated Ca²⁺ influx and subsequent CREB activation.