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  • br Acetylcholinesterase and cholinergic signaling The concep

    2019-07-24


    Acetylcholinesterase and cholinergic signaling The concept of a synapse between a neuron and an innervated cell, and the receptors that mediated their interaction, was developed by Bernard, Ehrlich, Sherrington, Langley and others (see [7], [8], [9]. It was long debated whether transmission of nerve impulses Donitriptan hydrochloride to muscle cells occurs by electrical or by chemical signals until the work of Otto Loewi and Henry Dale, later recognized by their Nobel Prize in 1936 [10]. The gains in understanding of various physiological processes by these early investigators and others were aided by using natural toxins. In fact, Loewi [11] considered the primary objective of pharmacology as “revealing physiological functions by the reactions of living matter to chemical agents”. While this narrow description does not encompass the multifold aspects of modern pharmacology, the experimental use of xenobiotics has played an essential role in gaining an understanding of neurotransmission and cholinergic signaling. Over a century ago, Dale [12] compared the effects of selected choline esters with the mushroom toxin, muscarine, and was the first to describe “muscarine-like” and “nicotine-like” actions. The relative potency of choline esters in isolated organ systems vs intact animals led him to posit that the “evanescence” of their effects could be due to rapid hydrolysis by an esterase. In Loewi’s classic studies [13], stimulating the vagus in a nerve-heart preparation in physiological solution triggered release of a substance called vagusstoff (i.e., vagus substance) that mimicked the effect of nerve stimulation when the fluid medium was transferred to a second heart with no vagal connection. Importantly, Loewi also showed that the effect of the vagal substance was (like that of acetylcholine) enhanced by eserine, a known inhibitor of ChEs [14], [15]. Soon thereafter, Dale and Dudley [16] reported the isolation of Donitriptan hydrochloride from tissue (horse spleen), confirming its endogenous presence. These studies and others laid groundwork for an enormous amount of research on the role of acetylcholine in synaptic signaling and its regulation by AChE. There is now a widespread consensus that AChE is the paramount or sole enzyme regulating neurotransmission in vertebrate cholinergic pathways that include brain, skeletal muscle and the autonomic nervous system. AChE serves this role in all mammals by selectively inactivating acetylcholine, within seconds or milliseconds after it is released from a presynaptic cholinergic neuron. AChE is one of the most efficient enzymes in the body, with a catalytic rate that approaches the limit of diffusion [17], [18]. AChE’s function appears equally important in brain and the periphery. This view is supported by the intensely concentrated localization of this enzyme at cholinergic synapses throughout the body, and by the diversity of effects elicited by inhibiting AChE either in the brain or in the peripheral compartment.
    Physiological role of BChE In contrast to the long-established and well-defined role of AChE in regulating cholinergic signaling, a true physiological function for BChE remained elusive over many decades. BChE exhibits much broader substrate specificity than AChE. For example it hydrolyzes butyrylcholine and acetylcholine while AChE only hydrolyzes the latter. Also, while BChE expression in many tissues exceeds that of AChE, it exists at much lower concentrations in the brain, skeletal muscle, and peripheral nerves [19]. Although exogenous butyrylcholine has been shown to modulate intrinsic cardiac neuron activity in canines [20], [21], to our knowledge no synapses in higher vertebrates use butyrylcholine as a neurotransmitter. In fact, a longstanding consensus holds that such synapses do not exist. Evidence to support that view is that, in our unpublished studies, selective inhibitors such as iso-OMPA (tetra isopropyl pyrophosphoramide) can completely inhibit BChE catalysis without eliciting obvious physiological disturbance. Not surprisingly, BChE knockout mice with no BChE expression appear perfectly healthy [22]. In particular, they show no apparent change in motor, autonomic or cognitive function. Under casual observation they are indistinguishable from wild-type mice. Moreover, there are isolated human populations who have been identified as completely lacking a functional BCHE gene, but again, by all accounts, they exhibit a normal phenotype. Their only physiologic difference from “wild-type” is an elevated risk when exposed to bioactive esters in food or ester-type muscle relaxants in the clinic [23], [24].