AKAP150 Contributes to Enhanced Vascular Tone by Facilitating Large-Conductance Ca 2+ -Activated K + Channel Remodeling in Hyperglycemia and Diabetes Mellitus
Copyright policy )AKAP150 Contributes to Enhanced Vascular Tone by Facilitating Large-Conductance Ca 2+ -Activated K + Channel Remodeling in Hyperglycemia and Diabetes Mellitus
Rationale : Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca 2+ -activated K + (BK Ca ) channel function. The scaffolding protein A-kinase anchoring protein 150 (AKAP150) is a key regulator of calcineurin (CaN), a phosphatase known to modulate the expression of the regulatory BK Ca β1 subunit. Whether AKAP150 mediates BK Ca channel suppression during hyperglycemia and diabetes mellitus is unknown. Objective : To test the hypothesis that AKAP150-dependent CaN signaling mediates BK Ca β1 downregulation and impaired vascular BK Ca channel function during hyperglycemia and diabetes mellitus. Methods and Results : We found that AKAP150 is an important determinant of BK Ca channel remodeling, CaN/nuclear factor of activated T-cells c3 (NFATc3) activation, and resistance artery constriction in hyperglycemic animals on high-fat diet. Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. d -glucose–dependent suppression of BK Ca channel β1 subunits required Ca 2+ influx via voltage-gated L-type Ca 2+ channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, high-fat diet mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BK Ca β1 subunits and attenuated high-fat diet–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 BK Ca channel remodeling, which contributes to vasoconstriction during diabetes mellitus.
- University of Mary United States
- University of California, San Francisco United States
- University of Colorado System United States
- University of Colorado Denver United States
- University of California, Davis United States
Inbred C57BL (mesh), Vascular (mesh), Large-Conductance Calcium-Activated Potassium Channel beta Subunits, Medical Physiology, A Kinase Anchor Proteins, Cardiorespiratory Medicine and Haematology, 3208 Medical Physiology (for-2020), Cardiovascular, Inbred C57BL, Muscle, Smooth, Vascular, Mice, 1103 Clinical Sciences (for), A Kinase Anchor Proteins (mesh), 2.1 Biological and endogenous factors, Animals (mesh), Toxins, Gene Knock-In Techniques, 32 Biomedical and Clinical Sciences (for-2020), calcineurin, Inbred BALB C, Mice, Inbred BALB C, Diabetes, Mice (mesh), ion channels, 3201 Cardiovascular medicine and haematology (for-2020), Experimental (mesh), potassium channels, Mutant Strains, Hypertension, Muscle, Peptides (mesh), Cardiovascular (rcdc), Smooth, Mutant Strains (mesh), Signal Transduction, hypertension, Inbred BALB C (mesh), 1.1 Normal biological development and functioning, Clinical Sciences, 610, Hyperglycemia (mesh), Biological (mesh), Cardiovascular medicine and haematology, Diabetes Mellitus, Experimental, Experimental, Vascular, 1102 Cardiorespiratory Medicine and Haematology (for), Diabetes Mellitus, Large-Conductance Calcium-Activated Potassium Channel beta Subunits (mesh), Dietary Fats (mesh), Animals, Large-Conductance Calcium-Activated Potassium Channels, Cardiovascular System & Hematology (science-metrix), Nutrition, Toxins, Biological, 1.1 Normal biological development and functioning (hrcs-rac), Large-Conductance Calcium-Activated Potassium Channels (mesh), Cardiovascular (hrcs-hc), NFATC Transcription Factors (mesh), Biomedical and Clinical Sciences, NFATC Transcription Factors, 2.1 Biological and endogenous factors (hrcs-rac), 3202 Clinical sciences (for-2020), Vasoconstriction (mesh), Biological, Dietary Fats, Mice, Mutant Strains, Gene Knock-In Techniques (mesh), Mice, Inbred C57BL, Nutrition (rcdc), Cardiovascular System & Hematology, Vasoconstriction, Hyperglycemia, Diabetes (rcdc), Signal Transduction (mesh), hyperglycemia, Peptides, Hypertension (mesh)
Inbred C57BL (mesh), Vascular (mesh), Large-Conductance Calcium-Activated Potassium Channel beta Subunits, Medical Physiology, A Kinase Anchor Proteins, Cardiorespiratory Medicine and Haematology, 3208 Medical Physiology (for-2020), Cardiovascular, Inbred C57BL, Muscle, Smooth, Vascular, Mice, 1103 Clinical Sciences (for), A Kinase Anchor Proteins (mesh), 2.1 Biological and endogenous factors, Animals (mesh), Toxins, Gene Knock-In Techniques, 32 Biomedical and Clinical Sciences (for-2020), calcineurin, Inbred BALB C, Mice, Inbred BALB C, Diabetes, Mice (mesh), ion channels, 3201 Cardiovascular medicine and haematology (for-2020), Experimental (mesh), potassium channels, Mutant Strains, Hypertension, Muscle, Peptides (mesh), Cardiovascular (rcdc), Smooth, Mutant Strains (mesh), Signal Transduction, hypertension, Inbred BALB C (mesh), 1.1 Normal biological development and functioning, Clinical Sciences, 610, Hyperglycemia (mesh), Biological (mesh), Cardiovascular medicine and haematology, Diabetes Mellitus, Experimental, Experimental, Vascular, 1102 Cardiorespiratory Medicine and Haematology (for), Diabetes Mellitus, Large-Conductance Calcium-Activated Potassium Channel beta Subunits (mesh), Dietary Fats (mesh), Animals, Large-Conductance Calcium-Activated Potassium Channels, Cardiovascular System & Hematology (science-metrix), Nutrition, Toxins, Biological, 1.1 Normal biological development and functioning (hrcs-rac), Large-Conductance Calcium-Activated Potassium Channels (mesh), Cardiovascular (hrcs-hc), NFATC Transcription Factors (mesh), Biomedical and Clinical Sciences, NFATC Transcription Factors, 2.1 Biological and endogenous factors (hrcs-rac), 3202 Clinical sciences (for-2020), Vasoconstriction (mesh), Biological, Dietary Fats, Mice, Mutant Strains, Gene Knock-In Techniques (mesh), Mice, Inbred C57BL, Nutrition (rcdc), Cardiovascular System & Hematology, Vasoconstriction, Hyperglycemia, Diabetes (rcdc), Signal Transduction (mesh), hyperglycemia, Peptides, Hypertension (mesh)
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