Ethanol Elevates Excitability of Superior Cervical Ganglion Neurons by Inhibiting Kv7 Channels in a Cell Type-Specific and PI(4,5)P2-Dependent Manner

Alcohol causes diverse acute and chronic symptoms that often lead to critical health problems. Exposure to ethanol alters the activities of sympathetic neurons that control the muscles, eyes, and blood vessels in the brain. Although recent studies have revealed the cellular targets of ethanol, such as ion channels, the molecular mechanism by which alcohol modulates the excitability of sympathetic neurons has not been determined. Here, we demonstrated that ethanol increased the discharge of membrane potentials in sympathetic neurons by inhibiting the M-type or Kv7 channel consisting of the Kv7.2/7.3 subunits, which were involved in determining the membrane potential and excitability of neurons. Three types of sympathetic neurons, classified by their threshold of activation and firing patterns, displayed distinct sensitivities to ethanol, which were negatively correlated with the size of the Kv7 current that differs depending on the type of neuron. Using a heterologous expression system, we further revealed that the inhibitory effects of ethanol on Kv7.2/7.3 currents were facilitated or diminished by adjusting the amount of plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). These results suggested that ethanol and PI(4,5)P2 modulated gating of the Kv7 channel in superior cervical ganglion neurons in an antagonistic manner, leading to regulation of the membrane potential and neuronal excitability, as well as the physiological functions mediated by sympathetic neurons.

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Electrophysiological and Morphological Diversity of Mouse Sympathetic Neurons

Journal of Neurophysiology ◽

10.1152/jn.1999.82.5.2747 ◽

1999 ◽

Vol 82 (5) ◽

pp. 2747-2764 ◽

Cited By ~ 61

Author(s):

Phillip Jobling ◽

Ian L. Gibbins

Keyword(s):

Tyrosine Hydroxylase ◽

Electrical Properties ◽

Superior Cervical Ganglion ◽

Sympathetic Neurons ◽

Inactivation Kinetics ◽

Celiac Ganglion ◽

Cervical Ganglion ◽

Firing Properties ◽

Ganglion Neurons ◽

Cell Capacitance

We have used multiple-labeling immunohistochemistry, intracellular dye-filling, and intracellular microelectrode recordings to characterize the morphological and electrical properties of sympathetic neurons in the superior cervical, thoracic, and celiac ganglia of mice. Neurochemical and morphological characteristics of neurons varied between ganglia. Thoracic sympathetic ganglia contained three main populations of neurons based on differential patterns of expression of immunoreactivity to tyrosine hydroxylase, neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). In the celiac ganglion, nearly all neurons contained immunoreactivity to both tyrosine hydroxylase and NPY. Both the overall size of the dendritic tree and the number of primary dendrites were greater in neurons from the thoracic and celiac ganglia compared with those from the superior cervical ganglion. The electrophysiological properties of sympathetic neurons depended more on their ganglion of origin rather than their probable targets. All neurons in the superior cervical ganglion had phasic firing properties and large afterhyperpolarizations (AHPs). In addition, 34% of these neurons displayed an afterdepolarization preceding the AHP. Superior cervical ganglion neurons had prominent I M, I A, and I Hcurrents and a linear current-voltage relationship between −60 and −110 mV. Neurons from the thoracic ganglia had significantly smaller action potentials, AHPs, and apparent cell capacitance compared with superior cervical ganglion neurons, and only 18% showed an afterdepolarization. All neurons in superior cervical ganglia and most neurons in celiac ganglia received at least one strong preganglionic input. Nearly one-half the neurons in the celiac ganglion had tonic firing properties, and another 15% had firing properties intermediate between those of tonic and phasic neurons. Most celiac neurons showed significant inward rectification below −90 mV. They also expressed I A, but with slower inactivation kinetics than that of superior cervical or thoracic neurons. Both phasic and tonic celiac ganglion neurons received synaptic inputs via the celiac nerves in addition to strong inputs via the splanchnic nerves. Multivariate statistical analysis revealed that the properties of the action potential, the AHP, and the apparent cell capacitance together were sufficient to correctly classify 80% of neurons according to their ganglion of origin. These results indicate that there is considerable heterogeneity in the morphological, neurochemical, and electrical properties of sympathetic neurons in mice. Although the morphological and neurochemical characteristics of the neurons are likely to be related to their peripheral projections, the expression of particular electrophysiological traits seems to be more closely related to the ganglia within which the neurons occur.

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Statins prevent cholinesterase inhibitor blockade of sympathetic α7-nAChR-mediated currents in rat superior cervical ganglion neurons

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00269.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. H1737-H1744 ◽

Cited By ~ 17

Author(s):

Mansoor Mozayan ◽

Tony J. F. Lee

Keyword(s):

Superior Cervical Ganglion ◽

Vascular Function ◽

Cerebral Arteries ◽

Neuronal Cultures ◽

Nerve Terminals ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Α7 Nachr ◽

Cervical Ganglion ◽

Ganglion Neurons

Statins are reported to be beneficial in treating a multitude of disorders including dementia due to Alzheimer disease (AD) and vascular dementia (VaD) with varying, yet-to-be determined mechanisms of actions. Although cholinesterase inhibitors (ChEIs) are still recommended as the primary drug of choice for AD and related diseases, their efficacy is frequently questioned. We recently reported that α7-neuronal acetylcholine nicotinic receptor (α7-nAChR)-mediated neurogenic vasodilation of porcine cerebral arteries was blocked by ChEIs, and this blockade was prevented by statin pretreatment. The exact mechanism of interaction between ChEIs and statins remains unclear. Activation of α7-nAChRs located on perivascular postganglionic sympathetic nerve terminals releases norepinephrine, which then acts on presynaptic β2-adrenoceptors located on neighboring nitrergic nerve terminals, resulting in nitric oxide release and vasodilation. The present study, therefore, was designed to determine whether interaction of ChEIs and statins occurs at the α7-nAChR level. We examined effects of concurrent application of ChEIs and statins on α7-nAChR-mediated inward currents in primary neuronal cultures of rat superior cervical ganglion cells, the origin of the perivascular sympathetic innervation to the cerebral arteries. The results indicated that physostigmine, neostigmine, and galantamine inhibited choline- and nicotine-induced whole cell currents in a concentration-dependent manner. This inhibition, which was noncompetitive in nature, was prevented by concurrent application of mevastatin and lovastatin in a concentration-dependent manner. These results suggest that statins protect α7-nAChR function directly at the receptor level. Since α7-nAChR is neuroprotective, having beneficial effects on memory and cerebral vascular function, its functional inhibition by ChEIs may explain in part the limitation of its effectiveness in AD and VaD therapy. Protection of α7-nAChR function from ChEI inhibition by concurrent administration of statins may provide an alternative strategy in improving the efficacy of AD and VaD therapy.

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Amperometric detection of stimulus-induced quantal release of catecholamines from cultured superior cervical ganglion neurons.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.92.15.6938 ◽

1995 ◽

Vol 92 (15) ◽

pp. 6938-6942 ◽

Cited By ~ 66

Author(s):

Z. Zhou ◽

S. Misler

Keyword(s):

Superior Cervical Ganglion ◽

Amperometric Detection ◽

Quantal Release ◽

Cervical Ganglion ◽

Ganglion Neurons

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Plasticity of postganglionic sympathetic neurons in the rat superior cervical ganglion after axotomy

Microscopy Research and Technique ◽

10.1002/jemt.1070290209 ◽

1994 ◽

Vol 29 (2) ◽

pp. 120-130 ◽

Cited By ~ 32

Author(s):

Lars Klimaschewski ◽

Thang D. Tran ◽

Rainer Nobiling ◽

Christine Heym

Keyword(s):

Superior Cervical Ganglion ◽

Sympathetic Neurons ◽

Cervical Ganglion

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Effect of d-sparteine on nicotinic acetylcholine receptors in rat superior cervical ganglion neurons

Neurophysiology ◽

10.1007/bf01054507 ◽

1994 ◽

Vol 25 (4) ◽

pp. 222-227 ◽

Cited By ~ 1

Author(s):

S. V. Voitenko ◽

S. L. Purnyn' ◽

V. I. Skok

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Superior Cervical Ganglion ◽

Acetylcholine Receptors ◽

Nicotinic Acetylcholine ◽

Cervical Ganglion ◽

Ganglion Neurons

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Postganglionic sympathetic neurons express endothelin

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.274.3.r873 ◽

1998 ◽

Vol 274 (3) ◽

pp. R873-R878 ◽

Cited By ~ 8

Author(s):

Deborah H. Damon

Keyword(s):

Spinal Cord ◽

Superior Cervical Ganglion ◽

Sympathetic Neurons ◽

Northern Analysis ◽

Rat Pups ◽

Cervical Ganglion ◽

Brain And Spinal Cord ◽

The Brain

Endothelin (ET) is a peptide originally identified as an endothelial-derived vasoconstrictor. It is now recognized that ET is produced by and acts on many other tissues including the brain and spinal cord, where it is believed to modulate neurotransmission. The present studies demonstrate that ET is synthesized by and secreted from postganglionic sympathetic neurons. With the use of Northern analysis, ET-1 mRNA was detected in cultures of sympathetic superior cervical ganglion (SCG) neurons isolated from 3- to 5-day old rat pups. ET-1 and ET-3 peptides were also detected in cultured SCG neurons using immunohistochemistry. ET-1 (50 pg/106 cells) and ET-3 (173 pg/106 cells) were detected by radioimmunoassay of media conditioned by cultured SCG. ET-1 (77 pg/mg protein) and ET-3 (30 pg/mg protein) were also detected by radioimmunoassay of extracts of adult SCG.

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