Transmission In Sympathetic Ganglia Research Articles

Impact of RAAS Receptors and Membrane-Bound Transporter System in the Left Ventricle during the Long-Term Control of Hypertension.

The Renin-Angiotensin-Aldosterone System (RAAS) has been implicated in systemic and neurogenic hypertension. The infusion of RAAS inhibitors blunted arterial pressure and efficacy of use-dependent synaptic transmission in sympathetic ganglia. The current investigation aims to elucidate the impact of RAAS-mediated receptors on left ventricular cardiomyocytes and the role of the sarcolemma-bound carrier system in the heart of the hypertensive transgene model. A significant increase in mRNA and the protein expression for angiotensin II (AngII) receptor subtype-1 (AT1R) was observed in (mREN2)27 transgenic compared to the normotensive rodents. Concurrently, there was an upregulation in AT1R and a downregulation in the MAS1 proto-oncogene protein receptor as well as the AngII subtype-2 receptor in hypertensive rodents. There were modifications in the expressions of sarcolemma Na+-K+-ATPase, Na+-Ca2+ exchanger, and Sarcoendoplasmic Reticulum Calcium ATPase in the transgenic hypertensive model. These observations suggest chronic RAAS activation led to a shift in receptor balance favoring augmented cardiac contractility and disruption in calcium handling through modifications of membrane-bound carrier proteins and blood pressure. The study provides insight into mechanisms underlying RAAS-mediated cardiac dysfunction and highlights the potential value of targeting the protective arm of AngII in hypertension.

Neurotransmission: peptide transmitters turn 36.

![Figure][1] Michael Nusbaum discusses the impact of Lily Yeh Jan and Yuh Nung Jan's classic paper ‘Peptidergic transmission in sympathetic ganglia of the frog’, published in The Journal of Physiology in 1982. The ability of neurons to communicate via the regulated release of

Pursuit of Neurotransmitter Functions: Being Attracted with Fascination of the Synapse.

In the beginning of the 1970s, only two chemical substances, acetylcholine and γ-aminobutyric acid (GABA), had been definitely established as neurotransmitters. Under such circumstances, I started my scientific career in Professor Masanori Otsuka's lab searching for the transmitter of primary sensory neurons. Until 1976, lines of evidence had accumulated indicating that the undecapeptide substance P could be released as a transmitter from primary afferent fibers into spinal synapses, although the substance P-mediated synaptic response had yet to be identified. Peripheral synapses could serve as a good model and thus, it was demonstrated in the prevertebral sympathetic ganglia by1985 that substance P released from axon collaterals of primary sensory neurons acts as the transmitter mediating non-cholinergic slow excitatory postsynaptic potential (EPSP). At that time, we also found that autonomic synapses were useful to uncover the transmitter role of the opioid peptide enkephalins, whose functions had been unknown since their discovery in 1975. Accordingly, enkephalins were found to serve a transmitter role in mediating presynaptic inhibition of cholinergic fast and non-cholinergic slow transmission in the prevertebral sympathetic ganglia. In 1990s, we attempted to devise a combined technique of brain slices and patch-clamp recordings. We applied it to study the regulatory mechanisms that operate around cerebellar GABAergic inhibitory synapses, because most of the studies then had centered on excitatory synapses and because inhibitory synapses are crucially involved in brain functions and disorders. Consequently, we discovered novel forms of heterosynaptic interactions, dual actions of a single transmitter, and receptor crosstalk, the details of which are described in this review.

HCN Channel Blockers Act Pre‐ and Post‐Synaptically to Inhibit Synaptic Transmission and Gain in the Rat Superior Cervical Sympathetic Ganglion

Hyperpolarization‐activated cation channels encoded by HCN subunits are permeable to Na+ and K+ ions and carry inward h‐currents. The h‐current (Ih) was originally discovered in the heart, where it is the principal pacemaker current. Ivabradine, a selective blocker of Ih, was approved in the US in 2015 as an adjunct to β‐adrenergic blockade for clinical management of heart failure. Recently we observed that sympathetic neurons in the rat superior cervical ganglion (SCG) express prominent Ih responses that can be blocked by ZD7288, another selective antagonist. The goal of the present study was to test the hypothesis that Ih modulates synaptic transmission in sympathetic ganglia. We did this using dissociated SCG neurons and using acutely isolated intact ganglia, treated with enzymes to permit whole‐cell recording, together with simultaneous presynaptic stimulation and extracellular recording. When synaptic transmission was elicited by submaximal 1 Hz stimulation in the isolated intact SCG, the extracellular postsynaptic compound action potential was inhibited by about 20% by 10–40 μM Ivabradine and by 10–20 μM ZD7288. In dissociated SCG neurons, we measured Ih under voltage clamp, fit the data to a Hodgkin‐Huxley model and then used the model to implement virtual Ih under dynamic clamp. When neurons were probed with virtual nicotinic fast EPSPs created with dynamic clamp, blocking Ih with 10–15 μM ZD7288 increased the threshold‐synaptic conductance (thresh‐gsyn) from 7.0 ± 0.9 nS to 12.1 ± 2.0 nS (p<0.0001) and decreased synaptic gain from 2.2 to 1.7 in response to noisy patterns of virtual synaptic activity that were designed to mimic physiological activity in vivo. This indicates that the native postsynaptic Ih normally enhances synaptic amplification to increase postsynaptic spike output by the SCG. When the native Ih was reconstituted with virtual Ih, synaptic amplification was restored. Shifting the voltage‐dependence of activation to mimic binding of cyclic AMP to HCN channels further modulated thresh‐gsyn and synaptic gain. To assess presynaptic actions of Ih, we then measured nicotinic cholinergic synaptic currents evoked by minimal presynaptic stimulation of the intact SCG. Ivabradine and ZD7288 both reduced peak EPSC amplitude and total charge by 40 to 50% while also increasing the failure rate. This indicates that native Ih normally enhances the probability of acetylcholine release and the amount of release by preganglionic terminals. Taken together the results suggest that clinical use of Ivabradine may have the heretofore unknown effect of reducing peripheral sympathetic activity through its pre‐ and postsynaptic effects on ganglionic transmission. This may have beneficial therapeutic consequences by countering the sympathetic hyperactivity that can drive human hypertension and that exacerbates the progression of heart failure.Support or Funding InformationSupported by the Great Rivers Affiliate of the American Heart Association through Grant‐in‐Aid 13GRNT1685007

Voltage-Sensitive K(+) Channels Inhibit Parasympathetic Ganglion Transmission and Vagal Control of Heart Rate in Hypertensive Rats.

Parasympathetic withdrawal plays an important role in the autonomic dysfunctions in hypertension. Since hyperpolarizing, voltage-sensitive K+ channels (KV) hamper transmitter release, elevated KV-activity may explain the disturbed vagal control of heart rate (HR) in hypertension. Here, the KV inhibitor 3,4-diaminopyridine was used to demonstrate the impact of KV on autonomic HR control. Cardiac output and HR were recorded by a flow probe on the ascending aorta in anesthetized, normotensive (WKY), and spontaneously hypertensive rats (SHR), and blood pressure by a femoral artery catheter. 3,4-diaminopyridine induced an initial bradycardia, which was greater in SHR than in WKY, followed by sustained tachycardia in both strains. The initial bradycardia was eliminated by acetylcholine synthesis inhibitor (hemicholinium-3) and nicotinic receptor antagonist/ganglion blocker (hexamethonium), and reversed to tachycardia by muscarinic receptor (mAchR) antagonist (atropine). The latter was abolished by sympatho-inhibition (reserpine). Reserpine also eliminated the late, 3,4-diaminopyridine-induced tachycardia in WKY, but induced a sustained atropine-sensitive bradycardia in SHR. Inhibition of the parasympathetic component with hemicholinium-3, hexamethonium, or atropine enhanced the late tachycardia in SHR, whereas hexamethonium reduced the tachycardia in WKY. In conclusion, 3,4-diaminopyridine-induced acetylcholine release, and thus enhanced parasympathetic ganglion transmission, with subsequent mAchR activation and bradycardia. 3,4-diaminopyridine also activated tachycardia, initially by enhancing sympathetic ganglion transmission, subsequently by activation of norepinephrine release from sympathetic nerve terminals. The 3,4-diaminopyridine-induced parasympathetic activation was stronger and more sustained in SHR, demonstrating an enhanced inhibitory control of KV on parasympathetic ganglion transmission. This enhanced KV activity may explain the dysfunctional vagal HR control in SHR.

Alpha2-adrenoceptor-independent inhibition of acetylcholine receptor channel and sodium channel by dexmedetomidine in rat superior cervical ganglion neurons

Both central and peripheral sympathetic nervous systems contribute to the cardiovascular effects of dexmedetomidine (DMED), a highly selective and widely used a2-adrenoceptor agonist for sedation, analgesia, and stress management. The central sympatholytic effects are augmented by peripheral inhibition of sympathetic ganglion transmission. The mechanism is not clear. In this research, using conventional patch-clamp recordings we investigated the direct effects of DMED on sodium (Na+) channel currents (INa) and nicotinic acetylcholine (ACh) receptor (nAChRs) channel currents (IACh) in rat superior cervical ganglion (SCG) neurons to explore the possible mechanisms of sympathetic ganglion transmission inhibition by DMED. DMED voltage-dependently suppressed INa with half maximal inhibitory concentration (IC50) values of 67.2±9.6μM and 26.1±5.3μM at holding potentials of −80mV and −60mV, respectively. The inhibition of Na+ channels by DMED was also frequency dependent. 100μM DMED shifted the Na+ channel inactivation curves to the hyperpolarizing direction by 9.8mV (P<0.01) and slowed the recovery from inactivation by 8.9ms (P<0.01), but no effects were seen on the shape of the current–voltage relationship or Na+ channels activation curves. DMED dose-dependently inhibited IACh with an IC50 value of 5.5±2.4μM in SCG neurons, and this inhibition was voltage-independent. DMED pretreatment followed by fast co-application of DMED and ACh produced a significantly larger IACh inhibition than without DMED pretreatment. Yohimbine, phentolamine, and atropine pretreatment did not alter the inhibitory effects of DMED on INa and IACh.In conclusion, DMED dose-dependently inhibits INa and IACh in rat SCG neurons by preferential binding to the inactivated state of the Na+ channels and the closed state (resting) of nAChR channels respectively. Both inhibitions are a2-adrenoceptor independent. Furthermore, the nAChR channels in rat SCG neurons are much more sensitive to inhibition by DMED than Na+ channels.

Bilirubin modulates acetylcholine receptors in rat superior cervical ganglionic neurons in a bidirectional manner.

Autonomic dysfunction as a partial contributing factor to cardiovascular instability in jaundiced patients is often associated with increased serum bilirubin levels. Whether increased serum bilirubin levels could directly inhibit sympathetic ganglion transmission by blocking neuronal nicotinic acetylcholine receptors (nAChRs) remains to be elucidated. Conventional patch-clamp recordings were used to study the effect of bilirubin on nAChRs currents from enzymatically dissociated rat superior cervical ganglia (SCG) neurons. The results showed that low concnetrations (0.5 and 2 μM) of bilirubin enhanced the peak ACh-evoked currents, while high concentrations (3 to 5.5 µM) of bilirubin suppressed the currents with an IC50 of 4 ± 0.5 μM. In addition, bilirubin decreased the extent of desensitization of nAChRs in a concentration-dependent manner. This inhibitory effect of bilirubin on nAChRs channel currents was non-competitive and voltage independent. Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89. These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade. Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients.

RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions.

Autonomic dysfunction is a serious complication of diabetes and can lead to cardiovascular abnormalities and premature death. It was recently proposed that autonomic dysfunction is triggered by oxidation-mediated inactivation of neuronal nicotinic acetylcholine receptors (nAChRs), impairing synaptic transmission in sympathetic ganglia and resulting in autonomic failure. We investigated whether the receptor for advanced glycation end products (RAGE) and its role in the generation of reactive oxygen species (ROS) could be contributing to the events that initiate sympathetic malfunction under high glucose conditions. Using biochemical, live imaging and electrophysiological tools we demonstrated that exposure of sympathetic neurons to high glucose increases RAGE expression and oxidative markers, and that incubation with RAGE ligands (e.g. AGEs, S100 and HMGB1) mimics both ROS elevation and nAChR inactivation. In contrast, co-treatment with either antioxidants or an anti-RAGE IgG prevented the inactivation of nAChRs. Lastly, a role for RAGE in this context was corroborated by the lack of sensitivity of sympathetic neurons from RAGE knock-out mice to high glucose. These data define a pivotal role for RAGE in initiating the events associated with exposure of sympathetic neurons to high glucose, and strongly support RAGE signaling as a potential therapeutic target in the autonomic complications associated with diabetes.

Autoimmune autonomic ganglionopathy

Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder of widespread autonomic failure. Approximately half of the patients with AAG have the autoantibodies against the neuronal nicotinic acetylcholine receptor (AChR) in autonomic ganglia. These ganglionic AChR antibodies have the potential to mediate the synaptic transmission in sympathetic, parasympathetic, and enteric ganglia. Therefore, seropositive AAG patients exhibit various autonomic symptoms. Extra-autonomic manifestations (coexistence with brain involvement, sensory disturbance, endocrine disorders, autoimmune diseases and tumors) are present in many patients with AAG. The nicotinic AChRs comprise a family of abundantly expressed ligand-gated cation channels found throughout the central and peripheral nervous systems. Moreover, limited manifestations of autoimmune dysautonomia including autoimmune gastrointestinal dysmotility are newly recognized clinical entity. Although combined immunomodulatory therapy is beneficial for almost all patients with AAG, several case reports of some AAG patients with small benefit exist. This review focuses on the recent progress in the clinical approaches of AAG and its related disorders involving the role of autoantibodies and clinical practice.

Sites of action of ghrelin receptor ligands in cardiovascular control

Circulating ghrelin reduces blood pressure, but the mechanism for this action is unknown. This study investigated whether ghrelin has direct vasodilator effects mediated through the growth hormone secretagogue receptor 1a (GHSR1a) and whether ghrelin reduces sympathetic nerve activity. Mice expressing enhanced green fluorescent protein under control of the promoter for growth hormone secretagogue receptor (GHSR) and RT-PCR were used to locate sites of receptor expression. Effects of ghrelin and the nonpeptide GHSR1a agonist capromorelin on rat arteries and on transmission in sympathetic ganglia were measured in vitro. In addition, rat blood pressure and sympathetic nerve activity responses to ghrelin were determined in vivo. In reporter mice, expression of GHSR was revealed at sites where it has been previously demonstrated (hypothalamic neurons, renal tubules, sympathetic preganglionic neurons) but not in any artery studied, including mesenteric, cerebral, and coronary arteries. In rat, RT-PCR detected GHSR1a mRNA expression in spinal cord and kidney but not in the aorta or in mesenteric arteries. Moreover, the aorta and mesenteric arteries from rats were not dilated by ghrelin or capromorelin at concentrations >100 times their EC(50) determined in cells transfected with human or rat GHSR1a. These agonists did not affect transmission from preganglionic sympathetic neurons that express GHSR1a. Intravenous application of ghrelin lowered blood pressure and decreased splanchnic nerve activity. It is concluded that the blood pressure reduction to ghrelin occurs concomitantly with a decrease in sympathetic nerve activity and is not caused by direct actions on blood vessels or by inhibition of transmission in sympathetic ganglia.

A Highly Conserved Cytoplasmic Cysteine Residue in the α4 Nicotinic Acetylcholine Receptor Is Palmitoylated and Regulates Protein Expression

Nicotinic acetylcholine receptor (nAChR) cell surface expression levels are modulated during nicotine dependence and multiple disorders of the nervous system, but the mechanisms underlying nAChR trafficking remain unclear. To determine the role of cysteine residues, including their palmitoylation, on neuronal α4 nAChR subunit maturation and cell surface trafficking, the cysteines in the two intracellular regions of the receptor were replaced with serines using site-directed mutagenesis. Palmitoylation is a post-translational modification that regulates membrane receptor trafficking and function. Metabolic labeling with [(3)H]palmitate determined that the cysteine in the cytoplasmic loop between transmembrane domains 1 and 2 (M1-M2) is palmitoylated. When this cysteine is mutated to a serine, producing a depalmitoylated α4 nAChR, total protein expression decreases, but surface expression increases compared with wild-type α4 levels, as determined by Western blotting and enzyme-linked immunoassays, respectively. The cysteines in the M3-M4 cytoplasmic loop do not appear to be palmitoylated, but replacing all of the cysteines in the loop with serines increases total and cell surface expression. When all of the intracellular cysteines in both loops are mutated to serines, there is no change in total expression, but there is an increase in surface expression. Calcium accumulation assays and high affinity binding for [(3)H]epibatidine determined that all mutants retain functional activity. Thus, our results identify a novel palmitoylation site on cysteine 273 in the M1-M2 loop of the α4 nAChR and determine that cysteines in both intracellular loops are regulatory factors in total and cell surface protein expression of the α4β2 nAChR.

Reactive oxygen species inactivate neuronal nicotinic acetylcholine receptors through a highly conserved cysteine near the intracellular mouth of the channel: implications for diseases that involve oxidative stress.

An intriguing feature of several nicotinic acetylcholine receptors (nAChRs) on neurons is that their subunits contain a highly conserved cysteine residue located near the intracellular mouth of the receptor pore. The work summarized in this review indicates that α3β4-containing and α4β2-containing neuronal nAChRs, and possibly other subtypes, are inactivated by elevations in intracellular reactive oxygen species (ROS). This review discusses a model for the molecular mechanisms that underlie this inactivation. In addition, we explore the implications of this mechanism in the context of complications that arise from diabetes. We review the evidence that diabetes elevates cytosolic ROS in sympathetic neurons and inactivates postsynaptic α3β4-containing nAChRs shortly after the onset of diabetes, leading to a depression of synaptic transmission in sympathetic ganglia, an impairment of sympathetic reflexes. These effects of ROS on nAChR function are due to the highly conserved Cys residues in the receptors: replacing the cysteine residues in α3 allow ganglionic transmission and sympathetic reflexes to function normally in diabetes. This example from diabetes suggests that other diseases involving oxidative stress, such as Parkinson's disease, could lead to the inactivation of nAChRs on neurons and disrupt cholinergic nicotinic signalling.

Intragastric administration of capsiate, a transient receptor potential channel agonist, triggers thermogenic sympathetic responses

The sympathetic thermoregulatory system controls the magnitude of adaptive thermogenesis in correspondence with the environmental temperature or the state of energy intake and plays a key role in determining the resultant energy storage. However, the nature of the trigger initiating this reflex arc remains to be determined. Here, using capsiate, a digestion-vulnerable capsaicin analog, we examined the involvement of specific activation of transient receptor potential (TRP) channels within the gastrointestinal tract in the thermogenic sympathetic system by measuring the efferent activity of the postganglionic sympathetic nerve innervating brown adipose tissue (BAT) in anesthetized rats. Intragastric administration of capsiate resulted in a time- and dose-dependent increase in integrated BAT sympathetic nerve activity (SNA) over 180 min, which was characterized by an emergence of sporadic high-activity phases composed of low-frequency bursts. This increase in BAT SNA was abolished by blockade of TRP channels as well as of sympathetic ganglionic transmission and was inhibited by ablation of the gastrointestinal vagus nerve. The activation of SNA was delimited to BAT and did not occur in the heart or pancreas. These results point to a neural pathway enabling the selective activation of the central network regulating the BAT SNA in response to a specific stimulation of gastrointestinal TRP channels and offer important implications for understanding the dietary-dependent regulation of energy metabolism and control of obesity.

Diabetes Depresses Synaptic Transmission in Sympathetic Ganglia by Inactivating nAChRs through a Conserved Intracellular Cysteine Residue

Most people with diabetes develop severe complications of the autonomic nervous system; yet, the underlying causes of many diabetic-induced dysautonomias are poorly understood. Here we explore the idea that these dysautonomias results, in part, from a defect in synaptic transmission. To test this idea, we investigated cultured sympathetic neurons and show that hyperglycemia inactivates nAChRs through a mechanism involving an elevation in reactive oxygen species and an interaction with highly conserved cysteine residues located near the intracellular mouth of the nAChR channel. Consistent with this, we show that diabetic mice have depressed ganglionic transmission and reduced sympathetic reflexes, whereas diabetic mice expressing mutant postsynaptic nAChRs that lack the conserved cysteine residues on the alpha3 subunit have normal synaptic transmission in sympathetic ganglia and normal sympathetic reflexes. Our work suggests a new model for diabetic-induced dysautonomias and identifies ganglionic nAChRs as targets of hyperglycemia-induced downstream signals.

Peripheral inflammation augments gap junction-mediated coupling among satellite glial cells in mouse sympathetic ganglia

Intercellular coupling by gap junctions is one of the main features of glial cells, but very little is known about this aspect of satellite glial cells (SGCs) in sympathetic ganglia. We used the dye coupling method to address this question in both a prevertebral ganglion (superior mesenteric) and a paravertebral ganglion (superior cervical) of mice. We found that in control ganglia, the incidence of dye coupling among SGCs that form the envelope around a given neuron was 10-20%, and coupling between SGCs around different envelopes was rare (1.5-3%). The dye injections also provided novel information on the structure of SGCs. Following peripheral inflammation, both types of coupling were increased, but most striking was the augmentation of coupling between SGCs forming envelopes around different neurons, which rose by 8-14.6-fold. This effect appeared to be non-systemic, and was blocked by the gap junction blocker carbenoxolone. These changes in SGCs may affect signal transmission and processing in sympathetic ganglia.

An Activity-Dependent Retrograde Signal Induces the Expression of the High-Affinity Choline Transporter in Cholinergic Neurons

A well-accepted view of developing circuits is that synapses must be active to mature and persist, whereas inactive synapses remain immature and are eventually eliminated. We question this long-standing view by investigating nonfunctional cholinergic nicotinic synapses in the superior cervical ganglia (SCG) of mice with a disruption in the alpha3 nicotinic receptor (nAChR) subunit gene, a gene essential for fast synaptic transmission in sympathetic ganglia. Using imaging and electrophysiology, we show that synapses persist for at least 2-3 months without postsynaptic activity; however, the presynaptic terminals lack high-affinity choline transporters (CHTs), and as a result, they are quickly depleted of transmitter. Moreover, we demonstrate with rescue experiments that CHT is induced by signals downstream of postsynaptic activity, converting immature terminals to mature terminals capable of sustaining transmitter release in response to high-frequency or continuous firing. Importantly, postsynaptic neurons must be continually active to maintain CHT in presynaptic terminals.

Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy

Nicotinic acetylcholine receptors (AChR) are ligand-gated cation channels that are present throughout the nervous system. The ganglionic (α3-type) neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic and enteric autonomic ganglia. Autonomic ganglia are an important site of neural integration and regulation of autonomic reflexes. Impaired cholinergic ganglionic synaptic transmission is one important cause of autonomic failure. Ganglionic AChR antibodies are found in many patients with autoimmune autonomic ganglionopathy (AAG). These antibodies recognize the α3 subunit of the ganglionic AChR, and thus do not bind non-specifically to other nicotinic AChR. Patients with high levels of ganglionic AChR antibodies typically present with rapid onset of severe autonomic failure, with orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction and sicca symptoms. Impaired pupillary light reflex is often seen. Like myasthenia gravis, AAG is an antibody-mediated neurological disorder. Antibodies from patients with AAG inhibit ganglionic AChR currents and impair transmission in autonomic ganglia. An animal model of AAG in the rabbit recapitulates the important clinical features of the human disease and provides additional evidence that AAG is an antibody-mediated disorder caused by impairment of synaptic transmission in autonomic ganglia.

Neuronal Acetylcholine Receptor Autoimmunity

Nicotinic acetylcholine receptors (AChRs) are ligand-gated cation channels that are present throughout the nervous system. The muscle AChR mediates transmission at the neuromuscular junction; antibodies against the muscle AChR are the cause of myasthenia gravis. There are numerous subtypes of AChRs present throughout the nervous system. These neuronal AChRs are closely related to the muscle AChR structurally, but are pharmacologically and immunologically distinct. The ganglionic (alpha3-type) neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic, and enteric autonomic ganglia. Ganglionic AChR antibodies are found in up to 50% of patients with autoimmune autonomic ganglionopathy (AAG). Patients with AAG present with severe autonomic failure. Major clinical features include orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction, and sicca symptoms. Impaired pupillary light reflex is often seen. Like myasthenia, AAG is an antibody-mediated neurological disorder. Patients may improve with plasma exchange treatment or other immunomodulatory treatment. Experimental AAG, which recapitulates many of the features of the human disease, can be induced in rabbits by immunization against the ganglionic AChR or by passive transfer of antibodies to mice. Ganglionic AChR IgG inhibits nicotinic membrane current in cultured neuroblastoma cells. Central nervous system neuronal AChRs may also be targets of autoimmunity. For example, antibodies against alpha7-type AChRs have been identified in a few patients with encephalitis. It is still unclear if antibodies against receptors in the central nervous system can directly cause disease.

Invited Article: Autonomic ganglia

Nicotinic acetylcholine receptors (AChR) are ligand-gated cation channels that are present throughout the nervous system. The muscle AChR mediates transmission at the neuromuscular junction; antibodies against the muscle AChR are the cause of myasthenia gravis. The ganglionic (alpha 3-type) neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic, and enteric autonomic ganglia. Impaired cholinergic ganglionic synaptic transmission is one important cause of autonomic failure. Pharmacologic enhancement of ganglionic synaptic transmission may be a novel way to improve autonomic function. Ganglionic AChR antibodies are found in patients with autoimmune autonomic ganglionopathy (AAG). Patients with AAG typically present with rapid onset of severe autonomic failure. Major clinical features include orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction, and sicca symptoms. Impaired pupillary light reflex is often seen. Like myasthenia, AAG is an antibody-mediated neurologic disorder. The disease can be reproduced in experimental animals by active immunization or passive antibody transfer. The patient may improve with plasma exchange treatment or other immunomodulatory treatment. Antibodies from patients with AAG inhibit ganglionic AChR currents. Other phenotypes of AAG are now recognized based on the results of antibody testing. These other presentations are generally associated with lower levels of ganglionic AChR antibodies. A chronic progressive form of AAG may resemble pure autonomic failure. Milder forms of dysautonomia, such as postural tachycardia syndrome, are associated with ganglionic AChR in 10-15% of cases. Since ganglionic synaptic transmission is a common pathway for all autonomic traffic, enhancement of autonomic function through inhibition of acetylcholinesterase is a potential specific therapeutic strategy for autonomic disorders. Increasing the strength of ganglionic transmission can ameliorate neurogenic orthostatic hypotension without aggravating supine hypertension. Recent evidence also suggests a potential role for acetylcholinesterase inhibitors in the treatment of postural tachycardia syndrome.

The Skok legacy and beyond: Molecular mechanisms of slow synaptic excitation in sympathetic ganglia

Vladimir Skok and his colleagues did much of the pioneering work on fast excitatory synaptic transmission in sympathetic ganglia and on nicotinic acetylcholine receptors that mediate fast transmission. I and my colleagues (including Alex Selyanko, one of Vladimir’s proteges) have studied the additional process of slow synaptic excitation that is mediated by the action of acetylcholine on muscarinic receptors. This results primarily from the closure of “M-channels,” a subset of voltage-gated potassium channels composed of Kv7.2 and Kv7.3 channel subunits. These channels require membrane phosphatidylinositol-4,5-bisphosphate (PIP2) for their opening, and their closure by muscarinic receptor activation is now thought to result from the reduction in PIP2 levels that follows receptor-induced PIP2 hydrolysis. The dynamics of these two forms of synaptic excitation are compared.