The Anticonvulsant Drug Retigabine Enhances M-current and Reduces Neuronal Excitability in Bullfrog Sympathetic Neurons

Abstract Approaches to control epilepsy, one of the most important idiopathic brain disorders, are of great importance for public health. We have previously shown that in sympathetic neurons the neuronal isoform of the serum and glucocorticoid-regulated kinase (SGK1.1) increases the M-current, a well-known target for seizure control. The effect of SGK1.1 activation on kainate-induced seizures and neuronal excitability was studied in transgenic mice that express a permanently active form of the kinase, using electroencephalogram recordings and electrophysiological measurements in hippocampal brain slices. Our results demonstrate that SGK1.1 activation leads to reduced seizure severity and lower mortality rates following status epilepticus, in an M-current–dependent manner. EEG is characterized by reduced number, shorter duration, and early termination of kainate-induced seizures in the hippocampus and cortex. Hippocampal neurons show decreased excitability associated to increased M-current, without altering basal synaptic transmission or other neuronal properties. Altogether, our results reveal a novel and selective anticonvulsant pathway that promptly terminates seizures, suggesting that SGK1.1 activation can be a potent factor to secure the brain against permanent neuronal damage associated to epilepsy.

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Neurons, Receptors, and Channels

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-010919-023755 ◽

2020 ◽

Vol 60 (1) ◽

pp. 9-30 ◽

Cited By ~ 1

Author(s):

David A. Brown

Keyword(s):

Messenger Rna ◽

Neuronal Excitability ◽

Single Channel ◽

Sympathetic Neurons ◽

Electrophysiological Recording ◽

Muscarinic Agonists ◽

M Current ◽

Antisense Knockdown ◽

Sympathetic Transmission ◽

Laboratory Life

Here, I recount some adventures that I and my colleagues have had over some 60 years since 1957 studying the effects of drugs and neurotransmitters on neuronal excitability and ion channel function, largely, but not exclusively, using sympathetic neurons as test objects. Studies include effects of centrally active drugs on sympathetic transmission; neuronal action and neuroglial uptake of GABA in the ganglia and brain; the action of muscarinic agonists on sympathetic neurons; the action of bradykinin on neuroblastoma-derived cells; and the identification of M-current as a target for muscarinic action, including experiments to determine its distribution, molecular composition, neurotransmitter sensitivity, and intracellular regulation by phospholipids and their hydrolysis products. Techniques used include electrophysiological recording (extracellular, intracellular microelectrode, whole-cell, and single-channel patch-clamp), autoradiography, messenger RNA and complementary DNA expression, antibody injection, antisense knockdown, and membrane-targeted lipidated peptides. I finish with some recollections about my scientific career, funding, and changes in laboratory life and pharmacology research over the past 60 years.

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NGF Inhibits M/KCNQ Currents and Selectively Alters Neuronal Excitability in Subsets of Sympathetic Neurons Depending on their M/KCNQ Current Background

The Journal of General Physiology ◽

10.1085/jgp.200709924 ◽

2008 ◽

Vol 131 (6) ◽

pp. 575-587 ◽

Cited By ~ 30

Author(s):

Zhanfeng Jia ◽

Junjie Bei ◽

Lise Rodat-Despoix ◽

Boyi Liu ◽

Qingzhong Jia ◽

...

Keyword(s):

Neuronal Excitability ◽

Sympathetic Neurons ◽

Critical Role ◽

Neuronal Cell ◽

Similar Proportion ◽

M Current ◽

Proliferation And Differentiation ◽

Cervical Ganglion ◽

Firing Properties ◽

G Protein Coupled

M/KCNQ currents play a critical role in the determination of neuronal excitability. Many neurotransmitters and peptides modulate M/KCNQ current and neuronal excitability through their G protein–coupled receptors. Nerve growth factor (NGF) activates its receptor, a member of receptor tyrosine kinase (RTK) superfamily, and crucially modulates neuronal cell survival, proliferation, and differentiation. In this study, we studied the effect of NGF on the neuronal (rat superior cervical ganglion, SCG) M/KCNQ currents and excitability. As reported before, subpopulation SCG neurons with distinct firing properties could be classified into tonic, phasic-1, and phasic-2 neurons. NGF inhibited M/KCNQ currents by similar proportion in all three classes of SCG neurons but increased the excitability only significantly in tonic SCG neurons. The effect of NGF on excitability correlated with a smaller M-current density in tonic neurons. The present study indicates that NGF is an M/KCNQ channel modulator and the characteristic modulation of the neuronal excitability by NGF may have important physiological implications.

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Hyperpolarizing shift of the M-current activation curve after washout of muscarine in bullfrog sympathetic neurons

Neuroscience Letters ◽

10.1016/0304-3940(96)12495-2 ◽

1996 ◽

Vol 207 (2) ◽

pp. 97-100 ◽

Cited By ~ 10

Author(s):

Takayuki Tokimasa ◽

Mark A. Simmons ◽

Carla R. Schneider ◽

Takashi Akasu

Keyword(s):

Sympathetic Neurons ◽

Activation Curve ◽

M Current ◽

Current Activation ◽

Hyperpolarizing Shift

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Possible role of phosphatidylinositol 4,5, bisphosphate in luteinizing hormone releasing hormone-mediated M-current inhibition in bullfrog sympathetic neurons

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2004.03786.x ◽

2004 ◽

Vol 20 (11) ◽

pp. 2990-2998 ◽

Cited By ~ 18

Author(s):

Christopher P. Ford ◽

Patrick L. Stemkowski ◽

Peter A. Smith

Keyword(s):

Luteinizing Hormone ◽

Sympathetic Neurons ◽

Luteinizing Hormone Releasing Hormone ◽

Releasing Hormone ◽

M Current

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Abstract P201: Negative Regulation Of PVN Pre-sympathetic Neuronal Activity By Resident Microglia

Hypertension ◽

10.1161/hyp.78.suppl_1.p201 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Peng Shi ◽

Yunfan Lin ◽

Qianqian Bi ◽

Guo Cheng ◽

Xiao Shen

Keyword(s):

Neuronal Excitability ◽

Sympathetic Neurons ◽

Potassium Currents ◽

Firing Frequency ◽

Electrophysiological Recording ◽

Recombinant Peptide ◽

Regulatory Circuits ◽

Brain Parenchymal ◽

Parenchymal Cells

Hypothalamic paraventricular nucleus (PVN) is a critical integrating region in controlling peripheral sympathetic tonicity. While the vast studies have unraveled the regulatory circuits affecting PVN pre-sympathetic neurons, local factors for maintaining the homeostasis of neuronal excitability are barely understood. In the present study we investigated the role of microglia, the primary resident immune cells of the CNS, in this context. By electrophysiological recording, we found that loss of resident microglia induced an increased firing frequency and attenuated outward potassium currents in the PVN pre-sympathetic neurons, tachycardia and impaired heart rate variability. Combining the transcriptomics analysis of the PVN microglia, we identified a releasable factor, which was dominantly expressed in microglia compared to other brain parenchymal cells. ICV infusion of the recombinant peptide restored potassium currents in the PVN pre-sympathetic neurons and autonomic function in microglia-depleted mice. In summary, our results provided a novel intrinsic regulatory mechanism by which microglia suppress neuronal over excitation in physiological condition.

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