Selective Down-regulation of KV2.1 Function Contributes to Enhanced Arterial Tone during Diabetes

Background: K-V channels in vascular smooth muscle cells (VSMCs) regulate arterial tone. Results: K(V)2.1 in VSMCs is down-regulated via AKAP150-CaN-dependent NFATc3 signaling during diabetes. Conclusion: Transcriptional suppression of K(V)2.1 contributes to enhanced arterial tone in diabetes. Significance: AKAP150-CaN-dependent activation of NFATc3 may be a general mechanism for transcriptional regulation of K+ channels, and a valuable target to prevent and treat diabetic vascular complications. Enhanced arterial tone is a leading cause of vascular complications during diabetes. Voltage-gated K+ (K-V) channels are key regulators of vascular smooth muscle cells (VSMCs) contractility and arterial tone. Whether impaired K-V channel function contributes to enhance arterial tone during diabetes is unclear. Here, we demonstrate a reduction in K-V-mediated currents (I-Kv) in VSMCs from a high fat diet (HFD) mouse model of type 2 diabetes. In particular, I-Kv sensitive to stromatoxin (ScTx), a potent K(V)2 blocker, were selectively reduced in diabetic VSMCs. This was associated with decreased K(V)2-mediated regulation of arterial tone and suppression of the K(V)2.1 subunit mRNA and protein in VSMCs/arteries isolated from HFD mice. We identified protein kinase A anchoring protein 150 (AKAP150), via targeting of the phosphatase calcineurin (CaN), and the transcription factor nuclear factor of activated T-cells c3 (NFATc3) as required determinants of K(V)2.1 suppression during diabetes. Interestingly, substantial reduction in transcript levels for K(V)2.1 preceded down-regulation of large conductance Ca2+-activated K+ (BKCa) channel 1 subunits, which are ultimately suppressed in chronic hyperglycemia to a similar extent. Together, our study supports the concept that transcriptional suppression of K(V)2.1 by activation of the AKAP150-CaN/NFATc3 signaling axis contributes to enhanced arterial tone during diabetes.