Fig. 5.

Scheme for the proposed mechanism for LS-dependent regulation of KCa3.1 and KCa2.3 expression. LS increases intracellular Ca²⁺ concentration ([Ca²⁺]_i) in ECs by stimulating Ca²⁺ release from endoplasmic reticulum (ER) and Ca²⁺ influx, which is maintained by KCa activation through membrane hyperpolarization (Em). Ca²⁺/CaM complex then activates CaMKK, leading to phosphorylation and activation of Akt, CaMK, and AMPK. Akt in turn phosphorylates p300 at Ser1834, which increases its histone acetyltransferase activity. Following its translocation to the nuclei, active p300 binds to transcription factors including CREB via KIX:KID domains complex and permits their access to promoter regions of KCa3.1 and KCa2.3 genes (e.g., CRE and AP-1 element) by opening chromatin in these regions via histone acetylation, in addition to a direct acetylation of the transcription factors.