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

Nieves‐Cintrón, Madeline; Nystoriak, Matthew A.; Prada, Maria Paz; Johnson, Kenneth E.; Fayer, William; Dell’Acqua, Mark L.; Scott, John D.; Navedo, Manuel F.

doi:10.1074/jbc.m114.622811

Cited by 32 publications

(56 citation statements)

References 47 publications

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“…Yet, LTCC potentiation in response to HG drives significant [Ca 2C ] i enhancement, as it seems to occur in WT myocytes. Note that during chronic elevations in extracellular glucose, as in diabetes, both E mindependent (e.g., PKA-mediated upregulation of LTCC activity 7 ) as well as E m -dependent (e.g., downregulation of K C channel activity leading to depolarization and further LTCC activation 9,12,13 ) mechanisms synergize to contribute to modulate [Ca 2C ] i in arterial myocytes. Indeed, our simulation studies showed that the increase in [Ca 2C ] i seen with concomitant inhibition of K C currents and LTCC potentiation is Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…-activated BK Ca a and b1 subunits, which regulate arterial myocyte excitability and are glucose-sensitive, [12][13][14][15] was similar between WT and S1928A arteries. 7 Changes in Ca V 1.2 expression are also unlikely, as the S1928A point mutation itself did not alter the abundance of Ca V 1.2.…”

Section: Cmentioning

confidence: 99%

“…The Kapela et al 3,12,13 Specifically, elevated glucose caused a 2-fold increase in LTCC conductance, whereas BK Ca and K V 2.1 currents were reduced by 58 and 63%, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia

et al. 2017

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Enhanced L-type Ca 2C channel (LTCC) activity in arterial myocytes contributes to vascular dysfunction during diabetes. Modulation of LTCC activity under hyperglycemic conditions could result from membrane potential-dependent and independent mechanisms. We have demonstrated that elevations in extracellular glucose (HG), similar to hyperglycemic conditions during diabetes, stimulate LTCC activity through phosphorylation of Ca V 1.2 at serine 1928. Prior studies have also shown that HG can suppress the activity of K C channels in arterial myocytes, which may contribute to vasoconstriction via membrane depolarization. Here, we used a mathematical model of membrane and Ca 2C dynamics in arterial myocytes to predict the relative roles of LTCC and K C channel activity in modulating global Ca 2C in response to HG. Our data revealed that abolishing LTCC potentiation normalizes [Ca 2C ] i , despite the concomitant reduction in K C currents in response to HG. These results suggest that LTCC stimulation may be the primary mechanism underlying vasoconstriction during hyperglycemia.

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Section: Resultsmentioning

confidence: 99%

Section: Cmentioning

confidence: 99%

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Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia

et al. 2017

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“…First- and second-order left anterior descending coronary arteries were immediately dissected in ice-cold buffer containing (in mM): 134 NaCl, 6 KCl, 1 MgCl 2 , 2 CaCl 2 , 10 HEPES, and 7 glucose, pH 7.4. Coronary arterial myocytes were isolated using enzymatic digestion procedures similar to those described previously [19]. Briefly, vessels were incubated in digestion buffer containing (in mM): 140 NaCl, 5 KCl, 2 MgCl 2 , 10 HEPES, 10 glucose, pH 7.4 for 1 min at 37°C, before incubation in digestion buffer containing 1 mg/mL papain (Worthington) and 1 mg/mL dithiothreitol (37°C, 5 min with gentle agitation) and then in digestion buffer containing 1.25 mg/mL collagenase type H (Sigma) and 1 mg/mL trypsin inhibitor (Sigma) (37°C, 5 min with gentle agitation).…”

Section: Methodsmentioning

confidence: 99%

“…Non-permeabilized cells were then blocked with 1.5% BSA in PBS for 45 min. Immunofluorescent labeling of freshly isolated arterial myocytes was performed as described previously [19] using a rabbit polyclonal antibody specific for an extracellular epitope of K V 1.5 (Alomone; APC-150). The secondary antibody was an Alexa Fluor 488-conjugated donkey anti-rabbit (Abcam; 5 mg/ml).…”

Section: Methodsmentioning

confidence: 99%

Heteromeric complexes of aldo-keto reductase auxiliary K V β subunits (AKR6A) regulate sarcolemmal localization of K V 1.5 in coronary arterial myocytes

Nystoriak

Zhang

Jagatheesan

et al. 2017

Chemico-Biological Interactions

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Redox-sensitive potassium channels consisting of the voltage-gated K+ (KV) channel pore subunit KV1.5 regulate resting membrane potential and thereby contractility of vascular smooth muscle cells. Members of the KV1 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 KVβ subunits that associate with native KV1.5 channels in the vasculature is unknown. Here, we examined mRNA and protein expression of KVβ subunits and tested whether KVβ isoforms interact with KV1.5 channels in murine coronary arteries. We detected KVβ1 (AKR6A3), KVβ2 (AKR6A5) and KVβ3 (AKR6A9) transcripts and KVβ1 and KVβ2 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 KV1.5/KVβ1, KV1.5/KVβ2 and KVβ1/β2 in coronary arterial myocytes. Confocal microscopy and membrane fractionation analyses suggest that arterial myocytes from KVβ2-null mice have reduced abundance of sarcolemmal KV1.5. Together, data suggest that in coronary arterial myocytes, KV1.5 channels predominantly associate with KVβ1 and KVβ2 proteins and that KVβ2 performs a chaperone function for KV1.5 channels in arterial myocytes, thereby facilitating Kv1α trafficking and membrane localization.

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Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Tykocki

Boerman

Jackson

2017

Comprehensive Physiology

270

347

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Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body’s tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes.

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

Cited by 32 publications

References 47 publications

Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia

Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia

Heteromeric complexes of aldo-keto reductase auxiliary K V β subunits (AKR6A) regulate sarcolemmal localization of K V 1.5 in coronary arterial myocytes

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

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