Heteromeric complexes of aldo-keto reductase auxiliary K_Vβ subunits (AKR6A) regulate sarcolemmal localization of K_V1.5 in coronary arterial myocytes.

Redox-sensitive potassium channels consisting of the voltage-gated K⁺ (K_V) channel pore subunit K_V1.5 regulate resting membrane potential and thereby contractility of vascular smooth muscle cells. Members of the K_V1 family associate with cytosolic auxiliary β subunits, which are members of the aldo-keto reductase (AKR) superfamily (AKR6A subfamily). The Kvβ subunits have been proposed to regulate Kv1 gating via pyridine nucleotide cofactor binding. However, the molecular identity of K_Vβ subunits that associate with native K_V1.5 channels in the vasculature is unknown. Here, we examined mRNA and protein expression of K_Vβ subunits and tested whether K_Vβ isoforms interact with K_V1.5 channels in murine coronary arteries. We detected K_Vβ1 (AKR6A3), K_Vβ2 (AKR6A5) and K_Vβ3 (AKR6A9) transcripts and K_Vβ1 and K_Vβ2 protein in left anterior descending coronary arteries by real time quantitative PCR and Western blot, respectively. In situ proximity ligation assays indicated abundant protein-protein interactions between K_V1.5/K_Vβ1, K_V1.5/K_Vβ2 and K_Vβ1/β2 in coronary arterial myocytes. Confocal microscopy and membrane fractionation analyses suggest that arterial myocytes from K_Vβ2-null mice have reduced abundance of sarcolemmal K_V1.5. Together, data suggest that in coronary arterial myocytes, K_V1.5 channels predominantly associate with K_Vβ1 and K_Vβ2 proteins and that K_Vβ2 performs a chaperone function for K_V1.5 channels in arterial myocytes, thereby facilitating Kv1α trafficking and membrane localization.

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