A-type K channels encoded by Kv4.2, Kv4.3 and Kv1.4 differentially regulate intrinsic excitability of cortical pyramidal neurons

Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8103, St Louis, MO 63110, USA.
The Journal of Physiology (Impact Factor: 5.04). 05/2012; 590(Pt 16):3877-90. DOI: 10.1113/jphysiol.2012.229013
Source: PubMed


Rapidly activating and rapidly inactivating voltage-gated A-type K+ currents, IA, are key determinants of neuronal excitability and several studies suggest a critical role for the Kv4.2 pore-forming α subunit in the generation of IA channels in hippocampal and cortical pyramidal neurons. The experiments here demonstrate that Kv4.2, Kv4.3 and Kv1.4 all contribute to the generation of IA channels in mature cortical pyramidal (CP) neurons and that Kv4.2-, Kv4.3- and Kv1.4-encoded IA channels play distinct roles in regulating the intrinsic excitability and the firing properties of mature CP neurons. In vivo loss of Kv4.2, for example, alters the input resistances, current thresholds for action potential generation and action potential repolarization of mature CP neurons. Elimination of Kv4.3 also prolongs action potential duration, whereas the input resistances and the current thresholds for action potential generation in Kv4.3−/− and WT CP neurons are indistinguishable. In addition, although increased repetitive firing was observed in both Kv4.2−/− and Kv4.3−/− CP neurons, the increases in Kv4.2−/− CP neurons were observed in response to small, but not large, amplitude depolarizing current injections, whereas firing rates were higher in Kv4.3−/− CP neurons only with large amplitude current injections. In vivo loss of Kv1.4, in contrast, had minimal effects on the intrinsic excitability and the firing properties of mature CP neurons. Comparison of the effects of pharmacological blockade of Kv4-encoded currents in Kv1.4−/− and WT CP neurons, however, revealed that Kv1.4-encoded IA channels do contribute to controlling resting membrane potentials, the regulation of current thresholds for action potential generation and repetitive firing rates in mature CP neurons.

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    • "In the RVLM of experimental models of CHF, there is reduced expression of the voltage-gated K + channel protein (Kv)4.3, that has been demonstrated in the RVLM of experimental models of CHF (Gao et al. 2010). This protein contributes to the generation of I A (Sonner and Stern 2007; Carrasquillo et al. 2012). In agreement with these findings, in vitro studies have demonstrated reduced I A amplitude and Kv4.3 expression following 6-h treatment of catecholaminergic CATH.a cells with Ang II (Gao et al. 2010). "
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    ABSTRACT: Increased central angiotensin II (Ang II) levels contribute to sympathoexcitation in cardiovascular disease states such as chronic heart failure and hypertension. One mechanism by which Ang II increases neuronal excitability is through a decrease in voltage-gated, rapidly inactivating K(+) current (IA); however, little is known about how Ang II signaling results in reduced IA. Brain-derived neurotrophic factor (BDNF) has also been demonstrated to decrease IA and has signaling components common to Ang II. Therefore, we hypothesized that Ang II-mediated suppression of voltage-gated K(+) currents is due, in part, to BDNF signaling. Differentiated CATH.a, catecholaminergic cell line treated with BDNF for 2 h exhibited a reduced IA in a manner similar to that of Ang II treatment as demonstrated by whole-cell patch-clamp analysis. Inhibiting BDNF signaling by pretreating neurons with an antibody against BDNF significantly attenuated the Ang II-induced reduction of IA. Inhibition of a common component of both BDNF and Ang II signaling, p38 MAPK, with SB-203580 attenuated the BDNF-mediated reductions in IA. These results implicate the involvement of BDNF signaling in Ang II-induced reductions of IA, which may cause increases in neuronal sensitivity and excitability. We therefore propose that BDNF may be a necessary component of the mechanism by which Ang II reduces IA in CATH.a cells.
    Full-text · Article · Nov 2015
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    • "K+ channel alterations may reflect the clinical antinociceptive action. A number of studies have shown that voltage-gated K+ channels have a major role in the regulation of neuronal excitability (21,22). "
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    ABSTRACT: In order to investigate the effect of sodium ferulate (SF) on voltage-activated K(+) channels, the delayed rectifier K(+) current (Ik) in PC12 rat pheochromocytoma cells was recorded using the automated patch-clamp method. The results indicated that following the application of SF, the Ik in PC12 cells was significantly decreased in a concentration-dependent manner. The analysis of activation kinetic curves and inactivation kinetic curves of Ik showed that SF had an effect on the activation and inactivation kinetics. Following the application of 15.3 μM SF, the activation curve of the Ik of PC12 cells was shifted to positive potentials and the inactivation curve of the Ik of PC12 cells was shifted to negative potentials. This study revealed that the delayed rectifier K(+) currents of PC12 cells were inhibited following SF treatment in a concentration-dependent manner. The mechanism may be associated with the delayed activation and enhanced inactivation of Ik-associated channels.
    Full-text · Article · Sep 2014 · Experimental and therapeutic medicine
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    • "We found in the present study that neuroinflammation in RVLM following systemic LPS infusion was associated with a redox-sensitive reduction in the expression of Kv4.3 channel protein because of microglial activation and the presence of COX-2 and cytokine. Kv4.3 contributes to the transient outward potassium current; and its activation leads to reduction in neuronal excitability by increasing the duration of action potential [57]. By reducing Kv4.3 channel protein expression, it is thus reasonable to speculate that neuroinflammation in RVLM promotes hypertension via sympathoexcitation that may result from a redox-sensitive increase in neuronal excitability. "
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    ABSTRACT: In addition to systemic inflammation, neuroinflammation in the brain, which enhances sympathetic drive, plays a significant role in cardiovascular diseases, including hypertension. Oxidative stress in rostral ventrolateral medulla (RVLM) that augments sympathetic outflow to blood vessels is involved in neural mechanism of hypertension. We investigated whether neuroinflammation and oxidative stress in RVLM contribute to hypertension following chronic systemic inflammation. In normotensive Sprague-Dawley rats, systemic inflammation was induced by infusion of Escherichia coli lipopolysaccharide (LPS) into the peritoneal cavity via an osmotic minipump. Systemic arterial pressure and heart rate were measured under conscious conditions by the non-invasive tail-cuff method. The level of the inflammatory markers in plasma or RVLM was analyzed by ELISA. Protein expression was evaluated by Western blot or immunohistochemistry. Tissue level of superoxide anion (O2·-) in RVLM was determined using the oxidation-sensitive fluorescent probe dihydroethidium. Pharmacological agents were delivered either via infusion into the cisterna magna with an osmotic minipump or microinjection bilaterally into RVLM. Intraperitoneal infusion of LPS (1.2 mg/kg/day) for 14 days promoted sustained hypertension and induced a significant increase in plasma level of C-reactive protein, tumor necrosis factor-α (TNF-α), or interleukin-1β (IL-1β). This LPS-induced systemic inflammation was accompanied by activation of microglia, augmentation of IL-1β, IL-6, or TNF-α protein expression, and O2·- production in RVLM, all of which were blunted by intracisternal infusion of a cycloxygenase-2 (COX-2) inhibitor, NS398; an inhibitor of microglial activation, minocycline; or a cytokine synthesis inhibitor, pentoxifylline. Neuroinflammation in RVLM was also associated with a COX-2-dependent downregulation of endothelial nitric oxide synthase and an upregulation of intercellular adhesion molecule-1. Finally, the LPS-promoted long-term pressor response and the reduction in expression of voltage-gated potassium channel, Kv4.3 in RVLM were antagonized by minocycline, NS398, pentoxifylline, or a superoxide dismutase mimetic, tempol, either infused into cisterna magna or microinjected bilaterally into RVLM. The same treatments, on the other hand, were ineffective against LPS-induced systemic inflammation. These results suggest that systemic inflammation activates microglia in RVLM to induce COX-2-dependent neuroinflammation that leads to an increase in O2·- production. The resultant oxidative stress in RVLM in turn mediates neurogenic hypertension.
    Full-text · Article · Sep 2012 · Journal of Neuroinflammation
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