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Carl J Pepine - One of the best experts on this subject based on the ideXlab platform.
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KCNMB1 genotype influences response to verapamil sr and adverse outcomes in the international verapamil sr trandolapril study invest
Pharmacogenetics and Genomics, 2007Co-Authors: Amber L Beitelshees, Yan Gong, Danxin Wang, Nicholas J Schork, Rhonda M Cooperdehoff, Taimour Y Langaee, Mark D Shriver, Wolfgang Sadee, Harm J Knot, Carl J PepineAbstract:ObjectivesWe sought to determine whether polymorphisms in the large-conductance calcium and voltage-dependent potassium (BK) channel β1 subunit gene, KCNMB1, are associated with blood pressure response to verapamil SR or adverse outcomes in the GENEtic substudy of the INternational VErapamil SR/tran
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variable blood pressure response to verapamil by KCNMB1 genotype
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Amber L Beitelshees, Yan Gong, Carl J Pepine, R M Dehoff, J I Moss, Julie A JohnsonAbstract:Background The gain-of-function Glu65Lys mutation in the KCNMB1 potassium channel subunit was found protective against diastolic HTN in a Spanish population and Val110Leu has been associated with baroreflex function. We sought to determine whether Glu65Lys or Val110Leu were associated with variable verapamil response in a substudy of the INVEST trial. Methods Genetic samples were obtained from 611 (170 untreated and 441 stable background therapy) INVEST patients in whom the addition of verapamil was the only change to their antihypertensive treatment (Tx). Codons 65 and 110 were genotyped by pyrosequencing. The GLM procedure, controlling for age, BMI, baseline BP/heart rate (HR), and race was used to compare BP/HR response to verapamil at 6 weeks by genotype. Results Minor allele frequencies were 0.12 and 0.09 for codon 65 and 110, respectively. No differences in BP or HR response to verapamil were present by genotype in the entire population. However, when compared only in patients untreated at baseline, codon 65 and 110 variant allele carriers experienced significantly greater SBP reductions to verapamil at 6 weeks than non-variant allele carriers. (See Table). Conclusion Our data suggest that codon 65 and 110 genotype may be important determinants of variable SBP response to verapamil monotherapy. Our data also suggest that background antihypertensive therapy may confound or influence pharmacogenetic associations. Clinical Pharmacology & Therapeutics (2005) 77, P97–P97; doi: 10.1016/j.clpt.2004.12.263 Table 1. Codon 65 genotype Tx SBP Tx HR Codon 110 genotype Tx SBP Tx HR Estimated adjusted means (95confidence intervals). * p=0.022. ** p=0.041. † p=0.098. Glu65Glu 140 (137, 142) 74 (72, 75) Val110Val 139 (137, 142) 75 (74, 76) Lys65 carrier 130 (122, 138)* 72 (68, 77) Leu110 carrier 130 (122, 139)** 71 (67, 75)†
Amber L Beitelshees - One of the best experts on this subject based on the ideXlab platform.
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KCNMB1 genotype influences response to verapamil sr and adverse outcomes in the international verapamil sr trandolapril study invest
Pharmacogenetics and Genomics, 2007Co-Authors: Amber L Beitelshees, Yan Gong, Danxin Wang, Nicholas J Schork, Rhonda M Cooperdehoff, Taimour Y Langaee, Mark D Shriver, Wolfgang Sadee, Harm J Knot, Carl J PepineAbstract:ObjectivesWe sought to determine whether polymorphisms in the large-conductance calcium and voltage-dependent potassium (BK) channel β1 subunit gene, KCNMB1, are associated with blood pressure response to verapamil SR or adverse outcomes in the GENEtic substudy of the INternational VErapamil SR/tran
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variable blood pressure response to verapamil by KCNMB1 genotype
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Amber L Beitelshees, Yan Gong, Carl J Pepine, R M Dehoff, J I Moss, Julie A JohnsonAbstract:Background The gain-of-function Glu65Lys mutation in the KCNMB1 potassium channel subunit was found protective against diastolic HTN in a Spanish population and Val110Leu has been associated with baroreflex function. We sought to determine whether Glu65Lys or Val110Leu were associated with variable verapamil response in a substudy of the INVEST trial. Methods Genetic samples were obtained from 611 (170 untreated and 441 stable background therapy) INVEST patients in whom the addition of verapamil was the only change to their antihypertensive treatment (Tx). Codons 65 and 110 were genotyped by pyrosequencing. The GLM procedure, controlling for age, BMI, baseline BP/heart rate (HR), and race was used to compare BP/HR response to verapamil at 6 weeks by genotype. Results Minor allele frequencies were 0.12 and 0.09 for codon 65 and 110, respectively. No differences in BP or HR response to verapamil were present by genotype in the entire population. However, when compared only in patients untreated at baseline, codon 65 and 110 variant allele carriers experienced significantly greater SBP reductions to verapamil at 6 weeks than non-variant allele carriers. (See Table). Conclusion Our data suggest that codon 65 and 110 genotype may be important determinants of variable SBP response to verapamil monotherapy. Our data also suggest that background antihypertensive therapy may confound or influence pharmacogenetic associations. Clinical Pharmacology & Therapeutics (2005) 77, P97–P97; doi: 10.1016/j.clpt.2004.12.263 Table 1. Codon 65 genotype Tx SBP Tx HR Codon 110 genotype Tx SBP Tx HR Estimated adjusted means (95confidence intervals). * p=0.022. ** p=0.041. † p=0.098. Glu65Glu 140 (137, 142) 74 (72, 75) Val110Val 139 (137, 142) 75 (74, 76) Lys65 carrier 130 (122, 138)* 72 (68, 77) Leu110 carrier 130 (122, 139)** 71 (67, 75)†
Ligia Toro - One of the best experts on this subject based on the ideXlab platform.
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mitobk ca is encoded by the kcnma1 gene and a splicing sequence defines its mitochondrial location
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Harpreet Singh, Andrea L Meredith, Jean C Bopassa, Enrico Stefani, Ligia ToroAbstract:The large-conductance Ca(2+)- and voltage-activated K(+) channel (BK(Ca), MaxiK), which is encoded by the Kcnma1 gene, is generally expressed at the plasma membrane of excitable and nonexcitable cells. However, in adult cardiomyocytes, a BK(Ca)-like channel activity has been reported in the mitochondria but not at the plasma membrane. The putative opening of this channel with the BK(Ca) agonist, NS1619, protects the heart from ischemic insult. However, the molecular origin of mitochondrial BK(Ca) (mitoBK(Ca)) is unknown because its linkage to Kcnma1 has been questioned on biochemical and molecular grounds. Here, we unequivocally demonstrate that the molecular correlate of mitoBK(Ca) is the Kcnma1 gene, which produces a protein that migrates at ∼140 kDa and arranges in clusters of ∼50 nm in purified mitochondria. Physiological experiments further support the origin of mitoBK(Ca) as a Kcnma1 product because NS1619-mediated cardioprotection was absent in Kcnma1 knockout mice. Finally, BKCa transcript analysis and expression in adult cardiomyocytes led to the discovery of a 50-aa C-terminal splice insert as essential for the mitochondrial targeting of mitoBK(Ca).
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β1 KCNMB1 subunits mediate lithocholate activation of large conductance ca2 activated k channels and dilation in small resistance size arteries
Molecular Pharmacology, 2007Co-Authors: Anna N Bukiya, Ligia Toro, Jianxi Liu, Alejandro M. DopicoAbstract:Among the nongenomic effects of steroids, control of vasomotion has received increasing attention. Lithocholate (LC) and other physiologically relevant cholane-derived steroids cause vasodilation, yet the molecular targets and mechanisms underlying this action remain largely unknown. We demonstrate that LC (45 μM) reversibly increases the diameter of pressurized resistance cerebral arteries by ∼10%, which would result in ∼30% increase in cerebral blood flow. LC action is independent of endothelial integrity, prevented by 55 nM iberiotoxin, and unmodified by 0.8 mM 4-aminopyridine, indicating that LC causes vasodilation via myocyte BK channels. Indeed, LC activates BK channels in isolated myocytes through a destabilization of channel long-closed states without modifying unitary conductance. LC channel activation occurs within a wide voltage range and at Ca 2+ concentrations reached in the myocyte at rest and during contraction. Channel accessory β 1 subunits, which are predominant in smooth muscle, are necessary for LC to modify channel activity. In contrast, β 4 subunits, which are predominant in neuronal tissues, fail to evoke LC sensitivity. LC activation of cbv1+β 1 and native BK channels display identical characteristics, including EC 50 (46 μM) and E max (≈300 μM) values, strongly suggesting that the cbv1+β 1 complex is necessary and sufficient to evoke LC action. Finally, intact arteries from β 1 subunit knockout mice fail to relax in response to LC, although they are able to respond to other vasodilators. This study pinpoints the BK β 1 subunit as the molecule that senses LC, which results in myocyte BK channel activation and, thus, endothelial-independent relaxation of small, resistance-size arteries.
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endocytic trafficking signals in kcnmb2 regulate surface expression of a large conductance voltage and ca2 activated k channel
Neuroscience, 2007Co-Authors: Mahsa Zarei, Enrico Stefani, N Cox, R J Wilson, Min Song, L V Colom, Hansgunther Knaus, Ligia ToroAbstract:Abstract Large conductance voltage and calcium-activated K+ channels play critical roles in neuronal excitability and vascular tone. Previously, we showed that coexpression of the transmembrane β2 subunit, KCNMB2, with the human pore-forming α subunit of the large conductance voltage and Ca2+-activated K+ channel (hSlo) yields inactivating currents similar to those observed in hippocampal neurons [ Hicks GA, Marrion NV (1998) Ca2+-dependent inactivation of large conductance Ca2+-activated K+ (BK) channels in rat hippocampal neurones produced by pore block from an associated particle. J Physiol (Lond) 508 (Pt 3):721–734; Wallner M, Meera P, Toro L (1999b) Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels: A transmembrane β-subunit homolog. Proc Natl Acad Sci U S A 96:4137–4142]. Herein, we report that coexpression of β2 subunit with hSlo can also modulate hSlo surface expression levels in HEK293T cells. We found that, when expressed alone, β2 subunit appears to reach the plasma membrane but also displays a distinct intracellular punctuated pattern that resembles endosomal compartments. β2 Subunit coexpression with hSlo causes two biological effects: i) a shift of hSlo’s intracellular expression pattern from a relatively diffuse to a distinct punctated cytoplasmic distribution overlapping β2 expression; and ii) a decrease of hSlo surface expression that surpassed an observed small decrease in total hSlo expression levels. β2 Site-directed mutagenesis studies revealed two putative endocytic signals at the C-terminus of β2 that can control expression levels of hSlo. In contrast, a β2 N-terminal consensus endocytic signal had no effect on hSlo expression levels. Thus, β2 subunit not only can influence hSlo currents but also has the ability to limit hSlo surface expression levels via an endocytic mechanism. This new mode of β2 modulation of hSlo may depend on particular coregulatory mechanisms in different cell types.
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KCNMB1 regulates surface expression of a voltage and ca2 activated k channel via endocytic trafficking signals
Neuroscience, 2006Co-Authors: B Toro, Enrico Stefani, Ligia Toro, N Cox, R J Wilson, Emilio R Garridosanabria, Masoud M ZareiAbstract:Voltage-dependent and calcium-activated K(+) (MaxiK, BK) channels are ubiquitously expressed and have various physiological roles including regulation of neurotransmitter release and smooth muscle tone. Coexpression of the pore-forming alpha (hSlo) subunit of MaxiK channels with a regulatory beta1 subunit (KCNMB1) produces noninactivating currents that are distinguished by high voltage/Ca(2+) sensitivities and altered pharmacology [McManus OB, Helms LM, Pallanck L, Ganetzky B, Swanson R, Leonard RJ (1995) Functional role of the beta subunit of high conductance calcium-activated potassium channels. Neuron 14:645-650; Wallner M, Meera P, Ottolia M, Kaczorowski G, Latorre R, Garcia ML, Stefani E, Toro L (1995) Characterization of and modulation by a beta-subunit of a human maxi K(Ca) channel cloned from myometrium. Receptors Channels 3:185-199]. We now show that beta1 can regulate hSlo traffic as well, resulting in decreased hSlo surface expression. beta1 subunit expressed alone is able to reach the plasma membrane; in addition, it exhibits a distinct intracellular punctated pattern that colocalizes with an endosomal marker. Coexpressing beta1 subunit with hSlo, switches hSlo's rather diffuse intracellular expression to a punctate cytoplasmic localization that overlaps beta1 expression. Furthermore, coexpressed beta1 subunit reduces steady-state hSlo surface expression. Site-directed mutagenesis underscores a role of a putative endocytic signal at the beta1 C-terminus in the control of hSlo surface expression. We propose that aside from its well-established role as regulator of hSlo electrical activity, beta1 can regulate hSlo expression levels by means of an endocytic mechanism. This highlights a new beta1 subunit feature that regulates hSlo channels by a trafficking mechanism.
Yan Gong - One of the best experts on this subject based on the ideXlab platform.
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KCNMB1 genotype influences response to verapamil sr and adverse outcomes in the international verapamil sr trandolapril study invest
Pharmacogenetics and Genomics, 2007Co-Authors: Amber L Beitelshees, Yan Gong, Danxin Wang, Nicholas J Schork, Rhonda M Cooperdehoff, Taimour Y Langaee, Mark D Shriver, Wolfgang Sadee, Harm J Knot, Carl J PepineAbstract:ObjectivesWe sought to determine whether polymorphisms in the large-conductance calcium and voltage-dependent potassium (BK) channel β1 subunit gene, KCNMB1, are associated with blood pressure response to verapamil SR or adverse outcomes in the GENEtic substudy of the INternational VErapamil SR/tran
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variable blood pressure response to verapamil by KCNMB1 genotype
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Amber L Beitelshees, Yan Gong, Carl J Pepine, R M Dehoff, J I Moss, Julie A JohnsonAbstract:Background The gain-of-function Glu65Lys mutation in the KCNMB1 potassium channel subunit was found protective against diastolic HTN in a Spanish population and Val110Leu has been associated with baroreflex function. We sought to determine whether Glu65Lys or Val110Leu were associated with variable verapamil response in a substudy of the INVEST trial. Methods Genetic samples were obtained from 611 (170 untreated and 441 stable background therapy) INVEST patients in whom the addition of verapamil was the only change to their antihypertensive treatment (Tx). Codons 65 and 110 were genotyped by pyrosequencing. The GLM procedure, controlling for age, BMI, baseline BP/heart rate (HR), and race was used to compare BP/HR response to verapamil at 6 weeks by genotype. Results Minor allele frequencies were 0.12 and 0.09 for codon 65 and 110, respectively. No differences in BP or HR response to verapamil were present by genotype in the entire population. However, when compared only in patients untreated at baseline, codon 65 and 110 variant allele carriers experienced significantly greater SBP reductions to verapamil at 6 weeks than non-variant allele carriers. (See Table). Conclusion Our data suggest that codon 65 and 110 genotype may be important determinants of variable SBP response to verapamil monotherapy. Our data also suggest that background antihypertensive therapy may confound or influence pharmacogenetic associations. Clinical Pharmacology & Therapeutics (2005) 77, P97–P97; doi: 10.1016/j.clpt.2004.12.263 Table 1. Codon 65 genotype Tx SBP Tx HR Codon 110 genotype Tx SBP Tx HR Estimated adjusted means (95confidence intervals). * p=0.022. ** p=0.041. † p=0.098. Glu65Glu 140 (137, 142) 74 (72, 75) Val110Val 139 (137, 142) 75 (74, 76) Lys65 carrier 130 (122, 138)* 72 (68, 77) Leu110 carrier 130 (122, 139)** 71 (67, 75)†
Steven C Sansom - One of the best experts on this subject based on the ideXlab platform.
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hypertension of KCNMB1 is linked to deficient k secretion and aldosteronism
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Richard P Grimm, Debra L Irsik, Deann C Settles, David J Holtzclaw, Steven C SansomAbstract:Mice lacking the β1-subunit (gene, KCNMB1; protein, BK-β1) of the large Ca-activated K channel (BK) are hypertensive. This phenotype is thought to result from diminished BK currents in vascular smooth muscle where BK-β1 is an ancillary subunit. However, the β1-subunit is also expressed in the renal connecting tubule (CNT), a segment of the aldosterone-sensitive distal nephron, where it associates with BK and facilitates K secretion. Because of the correlation between certain forms of hypertension and renal defects, particularly in the distal nephron, it was determined whether the hypertension of KCNMB1−/− has a renal origin. We found that KCNMB1−/− are hypertensive, volume expanded, and have reduced urinary K and Na clearances. These conditions are exacerbated when the animals are fed a high K diet (5% K; HK). Supplementing HK-fed KCNMB1−/− with eplerenone (mineralocorticoid receptor antagonist) corrected the fluid imbalance and more than 70% of the hypertension. Finally, plasma [aldo] was elevated in KCNMB1−/− under basal conditions (control diet, 0.6% K) and increased significantly more than wild type when fed the HK diet. We conclude that the majority of the hypertension of KCNMB1−/− is due to aldosteronism, resulting from renal potassium retention and hyperkalemia.