Low-level vagus nerve stimulation upregulates small conductance calcium-activated potassium channels in the stellate ganglion

Abstract

Background Small conductance calcium activated potassium (SK) channels are responsible for afterhyperpolarization that suppresses nerve discharges. Objectives To test the hypotheses that low-level vagus nerve stimulation (LL-VNS) leads to the upregulation of SK2 proteins in the LSG. Methods Six dogs (Group 1) underwent 1-wk LL-VNS of the left cervical vagus nerve. Five normal dogs (Group 2) were used as control. SK2 protein levels were examined by western blotting. The ratio between SK2 and glyceraldehydes-3-phosphate-dehydrogenase (GAPDH) levels was used as an arbitrary unit (AU). Results We found higher SK2 expression in Group 1 (0.124 ± 0.049 AU) than Group 2 (0.085 ± 0.031 AU, P < 0.05). Immunostaining showed that the density of nerve structures stained with SK2 antibody was also higher in Group 1 (11,546 ± 7,271 μm2/mm2) than in Group 2 (5,321 ± 3,164 μm2/mm2, P < 0.05). There were significantly more ganglion cells without immunoreactivity to TH in Group 1 (11.4 ± 2.3%) than Group 2 (4.9 ± 0.7%; P < 0.05). The TH-negative ganglion cells mostly stained positive for choline acetyltransferase (ChAT) (95.9 ± 2.8% in Group 1 and 86.1 ± 4.4% in Group 2, P = 0.10). Immunofluorescence confocal microscopy revealed a significant decrease in the SK2 staining in the cytosol but an increase in the SK2 staining on the membrane of the ganglion cells in Group 1 compared to Group 2. Conclusion Left LL-VNS results in the upregulation of SK2 proteins, increased SK2 protein expression in the cell membrane and the increased TH-negative (mostly ChAT-positive) ganglion cells in the LSG. These changes may underlie the antiarrhythmic efficacy of LL-VNS in ambulatory dogs.

Role of the Autonomic Nervous System in Modulating Cardiac Arrhythmias

“…A subsequent study by the same group showed that in the LSG, LL-VNS also resulted in the upregulation of small-conductance calcium-activated potassium channel type 2 and increased its expression in the cell membrane ( Figure 8B and 8C). 155 These changes may facilitate hyperpolarization of the ganglion cells and reduce the frequency of neuronal discharges. 156 Thus, LL-VNS can functionally and structurally remodel the LSG, which might explain some of its antiarrhythmic effects.…”

“…25,26 It causes histological remodeling of the LSG that in turns decreases the sympathetic outflow to the heart. 30,155 Additionally, VNS leads to a reduction of heart rate, which may be protective because this may attenuate ratedependent alterations in ventricular action potential duration, refractoriness, and dispersion of both factors. However, the anti-VF effect of VNS is reduced but not abolished during constant cardiac pacing, 34,179 suggesting that the decrease in heart rate is an important but not the only protective mechanism.…”

Cardiac Innervation and Sudden Cardiac Death

“…17, 87 It is of interest that vagal stimulation, which is being evaluated as a treatment for HF to prevent sudden death, leads to cholinergic transdifferentiation of stellate ganglion in dogs. 88 …”

SK channels and ventricular arrhythmias in heart failure

“…Shen et al (Shen et al, 2011) demonstrated that low-level vagus nerve stimulation reduced cardiac stellate ganglion activity and paroxysmal AF. The mechanism of the reduced stellate ganglion activity might be attributable in part to the upregulation of SK2 channels in the stellate ganglion (Shen et al, 2013). …”