AKAP150 Contributes to Enhanced Vascular Tone by Facilitating Large-Conductance Ca ²⁺ -Activated K ⁺ Channel Remodeling in Hyperglycemia and Diabetes Mellitus

Abstract

Rationale Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes may arise from impaired large conductance Ca2+-activated K+ (BKCa) channel function. The scaffolding protein AKAP150 is a key regulator of calcineurin (CaN), a phosphatase known to modulate expression of the regulatory BKCa β1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes is unknown. Objective To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes. Methods and Results We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/NFATc3 activation, and resistance artery constriction in hyperglycemic animals on high fat diet (HFD). Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. D-glucose-dependent suppression of BKCa channel β1 subunits required Ca2+ influx via voltage-gated L-type Ca2+ channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, HFD mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa β1 subunits, and attenuated HFD-induced elevation in arterial blood pressure. Conclusions Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling, which contributes to vasoconstriction during diabetes.

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

“…Previous reports have shown that in vitro, short term exposure of coronary, cerebral, and mesenteric arteries to extracellular glucose concentrations that resemble diabetic hyperglycemia (e.g. 20 mM) inhibit K V and BK Ca channel activity in VSMCs (11)(12)(13)(14)(15). Thus, inhibition of these channels may contribute to enhanced arterial tone and vascular complications during diabetes.…”

Vascular Dysfunction in Diabetes Mellitus

“…Diabetes mellitus reduces BK channel activity by ≥3 mechanisms. First, as demonstrated by Nystoriak et al, 2 through activation of calcineurin, dephosphorylated nuclear factor of activated T cells, c3 isoform (NFATc3) enters the nucleus where it inhibits transcription of the β1 subunit of BK, thereby reducing BK sensitivity to calcium. Second, diabetes mellitus-induced elevations in reactive oxygen species (ROS), particularly hydrogen peroxide, directly oxidize cysteine residues in the bowl region of the α subunit of BK to reduce opening.…”

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

“…AKAPs play roles in many more cellular processes whose dysregulation leads to disease. They are involved in complex mechanisms such as memory formation and blood pressure control [161,262,263] and tether different protein assemblies to various subcellular compartments [264]. Thus AKAPs are a rich source to be considered as pharmacological targets.…”