Browsing by Subject "potassium currents"

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    Apamin-Sensitive Calcium-Activated Potassium Currents in Rabbit Ventricles with Chronic Myocardial Infarction
    (Wiley Online Library, 2013-10-24) Lee, Young Soo; Chang, Po-Cheng; Hsueh, Chia-Hsiang; Maruyama, Mitsunori; Park, Hyung Wook; Rhee, Kyoung-Suk; Hsieh, Yu-Cheng; Shen, Changyu; Weiss, James N.; Chen, Zhenhui; Lin, Shien-Fong; Chen, Peng-Sheng; Department of Medicine, IU School of Medicine
    Introduction Apamin-sensitive small-conductance calcium-activated potassium current (IKAS) is increased in heart failure. It is unknown if myocardial infarction (MI) is also associated with an increase of IKAS. Methods and Results We performed Langendorff perfusion and optical mapping in 6 normal hearts and 10 hearts with chronic (5 weeks) MI. An additional 6 normal and 10 MI hearts were used for patch clamp studies. The infarct size was 25% [95% confidence interval, 20 to 31] and the left ventricular ejection fraction was 0.5 [0.46 to 0.54]. The rabbits did not have symptoms of heart failure. The action potential duration measured to 80% repolarization (APD80) in the peri-infarct zone (PZ) was150 [142 to 159] ms, significantly (p=0.01) shorter than in the normal ventricles (158 to 177] ms). The intracellular Ca transient duration was also shorter in the PZ (148 [139 to 157] ms) than in normal ventricles (168 [157 to 180] ms; P=0.017). Apamin prolonged the APD80 in PZ by 9.8 [5.5 to 14.1] %, which is greater than in normal ventricles (2.8 [1.3 to 4.3] %, p=0.006). Significant shortening of APD80 was observed at the cessation of rapid pacing in MI but not in normal ventricles. Apamin prevented postpacing APD80 shortening. Patch clamp studies showed that IKAS was significantly higher in the PZ cells (2.51 [1.55 to 3.47] pA/pF, N=17) than in the normal cells (1.08 [0.36 to 1.80] pA/pF, N=15, p=0.019). Conclusion We conclude that IKAS is increased in MI ventricles and contributes significantly to ventricular repolarization especially during tachycardia.
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    NEUROFIBROMIN, NERVE GROWTH FACTOR AND RAS: THEIR ROLES IN CONTROLLING THE EXCITABILITY OF MOUSE SENSORY NEURONS
    (2007-01-03T18:34:09Z) Wang, Yue; Nicol, Grant D.; Vasko, Michael R.; Clapp, D. Wade; Cummins, Theodore R.
    ABSTRACT Yue Wang Neurofibromin, nerve growth factor and Ras: their roles in controlling the excitability of mouse sensory neurons Neurofibromin, the product of the Nf1 gene, is a guanosine triphosphatase activating protein (GAP) for p21ras (Ras) that accelerates the conversion of active Ras-GTP to inactive Ras-GDP. It is likely that sensory neurons with reduced levels of neurofibromin have augmented Ras-GTP activity. In a mouse model with a heterozygous mutation of the Nf1 gene (Nf1+/-), the patch-clamp recording technique is used to investigate the role of neurofibromin in controlling the state of neuronal excitability. Sensory neurons isolated from adult Nf1+/- mice generate more APs in response to a ramp of depolarizing current compared to Nf1+/+ mice. In order to elucidate whether the activation of Ras underlies this augmented excitability, sensory neurons are exposed to nerve growth factor (NGF) that activates Ras. In Nf1+/+ neurons, exposure to NGF increases the production of APs. To examine whether activation of Ras contributes to the NGF-induced sensitization in Nf1+/+ neurons, an antibody that neutralizes Ras activity is internally perfused into neurons. The NGF-mediated augmentation of excitability is suppressed by the Ras-blocking antibody in Nf1+/+ neurons, suggesting the NGF-induced sensitization in Nf1+/+ neurons depends on the activation of Ras. Surprisingly, the excitability of Nf1+/- neurons is not altered by the blocking antibody, suggesting that this enhanced excitability may depend on previous activation of downstream effectors of Ras. To determine the mechanism giving rise to augmented excitability of Nf1+/- neurons, isolated membrane currents are examined. Consistent with the enhanced excitability of Nf1+/- neurons, the peak current density of tetrodotoxin-resistant (TTX-R) and TTX-sensitive (TTX-S) sodium currents (INa) are significantly larger than in Nf1+/+ neurons. Although the voltage for half-maximal activation (V0.5) is not different, there is a significant depolarizing shift in the V0.5 for steady-state inactivation of INa in Nf1+/- neurons. In summary, these results demonstrate that the enhanced production of APs in Nf1+/- neurons results from a larger current amplitude and a depolarized voltage dependence of steady-state inactivation of INa that leads to more sodium channels being available for the subsequent firing of APs. My investigation supports the idea that regulation of channels by the Ras cascade is an important determinant of neuronal excitability. Grant D. Nicol, Ph.D, Chair