Dynamic regulation of potassium channel-associated aldo-keto reductase controls redox-dependent vasodilation

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Voltage-gated potassium channels of the Kv1 family in vascular smooth muscle are key determinants of membrane potential and arterial tone. Their activity is modulated by intracellular Kvβ subunits, including Kvβ2, an aldo-keto reductase (AKR) that links pyridine nucleotide redox state to channel function. Here, we identify Kvβ2 catalytic activity as an essential regulator of vascular Kv1 channel gating and redox-sensitive vasodilation that is dynamically modulated by protein kinase C (PKC). Using patch-clamp electrophysiology, we found that the endogenous AKR substrate methylglyoxal (MGO) increases Kv1 channel open probability in the presence of NADPH, whereas this effect is lost in cells expressing a catalytically inactive Kvβ2 subunit. Biochemical studies demonstrated Kvβ2 as a phosphorylation target, and PKCα-mediated phosphorylation significantly suppressed its catalytic activity. Consistent with this, cellular PKC activation with phorbol 12-myristate 13-acetate (PMA) prevented NADPH/MGO-induced potentiation of Kv1 channel activity and abolished Kv-dependent vasodilation triggered by L-lactate in mesenteric arteries. Mechanistically, Ser266 emerged as a key PKC-responsive site: molecular dynamics simulations indicated that phosphorylation at Ser266 may relax the Kvβ2 cofactor binding pocket, phosphomimetic modification reduced apparent NADPH binding affinity and slowed catalysis, and the S266A mutation increased basal catalytic activity while preventing PKCα-dependent suppression. Together, these findings identify a post-translational mechanism by which PKC dynamically regulates Kvβ2 enzymatic control of Kv1 channel behavior, linking metabolic redox state to vasomotor responsiveness. This redox-enzymatic signaling axis broadens our understanding of ion channel regulation in vascular physiology and may be relevant to diseases associated with microvascular dysfunction and heightened PKC signaling.