Slow channel syndrome

Slow-channel syndrome. Abnormally long-lived openings of mutant AChR channels result in prolonged endplate currents and potentials, which in turn elicit one or more repetitive muscle action potentials of lower amplitude that decrement. The morphologic consequences stem from prolonged activation of the AChR channel that causes cationic overload of the postsynaptic region - the endplate myopathy - with Ca2+ accumulation, destruction of the junctional folds, nuclear apoptosis, and vacuolar degeneration of the terminal. Some slow-channel mutations in the transmembrane domain of the AChR render the channel leaky by stabilization of the open state, which is populated even in the absence of ACh. Curiously, some slow-channel mutants can be opened by choline even at the concentrations that are normally present in serum. Quinidine, an open-channel blocker of the AchR, is used for therapy. 

Fast-channel syndrome. The clinical features resemble those of autoimmune myasthenia gravis (see below) with variable severity. Conversely to what is found in slow-channel syndrome, the open state of the AChR is destabilized, manifesting as fast dissociation of ACh from the receptor and/or excessively reduced open times. One mutation has also caused multiple congenital joint contractures owing to fetal hypomotility in utero. In most cases, the mutant allele causing the kinetic abnormality... 

Cdiannel problems 2, The acetylcholine receptor channel can also undergo mutation leading to fast-channel syndrome (I XIS). with clinical manifestations similar to those of slow-channel syndrome (S( S), What would the recordings of ion movement look like in this syndrome Suggest a biochemical explanation... 

This mutation is one of a class of mutations that result in slow channel syndrome (SCS). The results suggest a defect in channel closing so the channel remains open for prolonged periods. Alternatively, the channel may have a higher affinity for acetylcholine than does the control channel. 

Engel AG, Ohno K, Milone M et al 1996 New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum Mol Genet 5 1217-1227 ... 

Constipation may be caused by slow intestinal transition, pelvic floor dysfunction, bowel dysfunction like irritable Bowel syndrome and tumours, but can also be secondary to other diseases and life conditions. Many medicines cause constipation, for example opiates, calcium channel blockers and drugs with anticholinergic effects, e.g. antidepressants. 

Epilepsy affects 0.5% of the world s population and can have a multitude of underlying etiologies, including several mutations in CNS sodium channels. Sodium channel mutations linked to human epileptic syndromes typically shift activation to more hyperpolarized potentials, slow inactivation kinetics, accelerate recovery from inactivation, and/or increase the persistent current [48]. Seemingly paradoxically, some mutations appear to result in non-functional channels [48-50]. 

Cesium exhibits marked effects on the nervous system, both peripherally and centrally. This may be the consequence of the purported interchangeability of cesium with other group I metals. Certainly cesium ions will increase the frequency of miniature end-plate potentials, thought to be due to the slow entry of cesium ions into the nerve terminal [32]. In the central nervous system, it seems that cesium can share the same receptor as glycine and exerts its effects by activating the same chloride channel as the inhibitory neurotransmitter, glycine [33]. Indeed, in consequence of this action, cesium has been implicated as a causative agent of some epileptiform seizures [34]. More recently, pretreatment of rats with cesium chloride, followed by administration of the monoamine oxidase inhibitor tranylcypramine, has been shown to enhance 5-hydroxytryptamine (5-HT) behavioral syndrome. This may be due to either an increased amount of 5-HT synthesis and/or release, or a direct enhancement of the postsynaptic action of 5-HT [34b]. 

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