thyrotropin receptor It is now known that cholinergic signal
It is now known that cholinergic signaling plays a vital role in controlling many peripheral functions including skeletal and smooth muscle contraction, autonomic postganglionic neuron activation, parasympathetic end-organ activation (e.g., salivary, lacrimal and bronchial glands), regulation of cardiac activity, and others. Fig. 1 diagrams peripheral motor and autonomic functions regulated by cholinergic signaling and illustrates relationships among cholinergic receptor activation, acetylcholinesterase activity, and functional responses. As noted previously, early research on cholinergic signaling was focused on the neuromuscular junction. Claude Bernard’s studies of neuromuscular blockade by the arrow poison, curare, were instrumental in developing the concept of nerve-muscle synapses . Adequate control of muscle tone is an essential goal in many surgical and emergency settings. Neuromuscular blocking agents have been extensively used to facilitate tracheal intubations, perform endoscopic evaluations and maintain immobility during surgery. Curare acts as a competitive, non-depolarizing blocker of nicotinic receptors at the neuromuscular junction. A variety of non-depolarizing neuromuscular blockers such as atracurium, vecuronium and rocuronium have been developed and implemented clinically to block neuromuscular transmission. When neuromuscular blockade is no longer needed, it has to be reversed for rapid recovery of muscle tone. Cholinesterase inhibitors (e.g., neostigmine) have been used to reverse the effects of these non-depolarizing neuromuscular blocking agents. While cholinesterase inhibitors are still used for this purpose, a reversal agent that does not act by inhibiting acetylcholinesterase (sugammadex, a cyclodextrin-based scavenger) is being increasingly used to reverse the effects of rocuronium and vecuronium , . In thyrotropin receptor to the non-depolarizing receptor blockers, succinylcholine, a structural analog of acetylcholine, is a depolarizing blocker that remains the gold standard for neuromuscular blockade in rapid procedures such as emergency intubations . Succinylcholine’s neuromuscular blockade is ordinarily reversed very quickly by the catalytic activity of plasma BChE . However, as noted above, problems did arise in some individuals, owing to genetic differences in the catalytic activity of their BChE , . Obviously, a cholinesterase inhibitor would be of no use in reversing neuromuscular blockade induced by succinylcholine, and could in fact be counterproductive. But inhibiting acetylcholine breakdown by blocking AChE activity may be beneficial in disorders wherein acetylcholine signaling is impaired . One clinical condition that can be improved by blocking acetylcholine hydrolysis is myasthenia gravis, a group of neuromuscular disorders involving autoimmune-mediated destruction of neuromuscular nicotinic receptors or associated proteins at the neuromuscular junction . By virtue of their ability to block degradation of acetylcholine at the neuromuscular junction and enhance the activation of nicotinic receptors, cholinesterase inhibitors (e.g., pyridostigmine) have been used for decades to enhance muscular performance in human and veterinary patients . However, one form of myasthenia gravis, associated with antibodies to muscle-specific kinase, does not benefit from blocking AChE and symptoms may in fact be exacerbated by cholinesterase inhibitors. Another cholinesterase inhibitor, the rapid-acting and reversible inhibitor edrophonium (Tensilon®), is often used in the Tensilon test to diagnose myasthenia gravis. Intravenous administration of edrophonium leads to a rapid (seconds) and dramatic, short-term improvement in muscle tone. Edrophonium may also be helpful in diagnosing other neuromuscular disorders, such as cervical dystonia and blepharospasm , . Cholinesterase inhibitors can be helpful in treating glaucoma, a leading cause of blindness worldwide . Generally, increased intraocular pressure from aqueous humor accumulation leads to degeneration of the optic nerve and retinal ganglion cells. Strategies that reduce intraocular pressure are the only approaches proven to treat most forms of glaucoma . Ocular administration of an anti-ChE can facilitate contraction of the ciliary muscle and increase the flow of aqueous humor through the trabecular meshwork to reduce intraocular pressure. Other drugs, e.g., sulfonamide carbonic anhydrase inhibitors such as acetazolamide and dorzolamide that decrease the formation of aqueous humor and prostaglandin F analogs (e.g., latanoprost, bimatoprost) that enhance aqueous humor outflow have largely supplanted cholinesterase inhibitors for these conditions . Interestingly, the reversible cholinesterase inhibitor galantamine was recently shown to protect retinal ganglion cells and improve local blood flow in experimental models of glaucoma, but in a manner independent of intraocular pressure , .