Nicotinic cholinergic structure

Elgoyhen AB, Vetter DE, Katz E, RotWinCV, Heinemann SF, Boulter J (2001) alO a determinant of nicotinic cholinergic receptor function in mammalian vestibular and chochlear mechanosen-sory hair cells. Proc Natl Acad Sci 98 3501-3506 Fabian-Fine R, Skehel P, Erington ML, Davies HA, Sher E, Stewart MG, Fine A (2001) Ultra-structural distribution of the a7 nicotinic acetylcholine receptor subunit in rat hippocampus. J Neurosci 21 7993-8003... 

B. M. Conti-Tronconi, M. A. Raftery (1982). The nicotinic cholinergic receptor correlations of molecular structure with functional properties. Annu. Rev. Biochem. 5P. 491-530. 

Glennon, R.A., Dukat, M., 1999b. Nicotine analogs structure-affinity relationships for central acetyl-cholinergic receptor binding. In Yamamoto, I., Casida, J.E. (Eds.), Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor. Spinger-Verlag, Tokyo, 237-252. 

Many compounds structurally related to nicotine have been tested for activity with the nicotinic cholinergic receptor but. as with the (+)- isomer of nicotine, they generally less activity as agonists, while showing other activities such as blocking the ion channel. Metabolic derivatives of nicotine may account for some of the actions attributed to nicotine, but not necessarily actions at the nicotinic receptor [162]. Nicotine does, indeed, act on other tissues and some of these actions will be cited in other sections of this review. 

Pre- and postsynaptic elements, therefore, play a key role in excitation of the brain. We focus here on prototypes of a presynaptic and a postsynaptic element. As an example of a presynaptic element, we selected the dihydropyr-idine-sensitive calcium channel, a member of the superfamily of voltage-gated channel proteins. The most extensively studied membrane protein, the nicotinic cholinergic receptor, which belongs to the family of ligand-gated channels, is present in the postsynaptic membrane. These two examples are used to describe a strategy that aims to identify sequence-specific motifs that are responsible for the performance of unique functions and to outline an experimental approach to evaluate identified structural motifs. 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

In contrast to all this negativity, it must be acknowledged that more is known about the structure and function of cholinergic receptors and synapses, especially the nicotinic ones, than for the receptors of any other NT. It is unfortunate that nicotinic synapses are not very common in the CNS. 

Acetylcholine receptors have been classified into sub-types based on early studies of pharmacologic selectivity. Long before structures were known, two crude alkaloid fractions, containing nicotine and muscarine (Fig. 11-2), were used to subclassify receptors in the cholinergic nervous system (Fig. 11-3). The greatly different... 

FIGURE 11-3 Structure of compounds important to the classification of receptor subtypes at cholinergic synapses. Compounds are subdivided as nicotinic (N) and muscarinic (Ad). The compounds interacting with nicotinic receptors are subdivided further according to whether they are neuromuscular (N,) or ganglionic (N2). Compounds with muscarinic subtype selectivity (M M2, M3, M4) are also noted. 

The intrinsic complexity and the multiplicity of cholinergic receptors became evident upon elucidation of their primary structures. In the CNS, at least nine different sequences of a subunits and three different sequences of (3 subunits of the nicotinic receptor have been identified [10, 11]. Expression of the cloned genes encoding certain subunit combinations yields functional receptors with different sensitivities toward various toxins and agonists. 

Thus, cholinergic receptor classification can be considered in terms of three stages of development. Initially, Dale [2] distinguished nicotinic and muscarinic receptor subtypes with crude alkaloids. Then, chemical synthesis and structure-activity relationships clearly revealed that nicotinic and muscarinic receptors were heterogeneous, but chemical selectivity could not come close to uncovering the true diversity of receptor subtypes. Lastly, analysis of subtypes came from molecular cloning, making possible the classification of receptors on the basis of primary structure (Fig. 11-2). 

Paton WDM, Zaimis EJ (1949) The pharmacological actions of polymethylene bistrimethylammo-nium salts. Br J Pharmacol Chemother 4 381 00 Patrick J, Stallcup WB (1977) a-Bungarotoxin binding and cholinergic receptor function on a rat sympathetic nerve line. J Biol Chem 252 8629-8633 Patrick J, Boulter J, Deneris E, Wada K, Wada E, Connolly J, Swanson L, Heinemann S (1989) Structure and function of neuronal nicotinic acetylcholine receptors deduced from cDNA clones. Prog Brain Res 79 27-33... 

The issue of drug selectivity is related closely to the fact that many receptor populations can be divided into various subtypes according to specific structural and functional differences between subgroups of the receptor. A primary example is the cholinergic (acetylcholine) receptor found on various tissues throughout the body. These receptors can be classified into two primary subtypes muscarinic and nicotinic. Acetylcholine will bind to either subtype, but drugs such as nicotine will bind preferentially to the nicotinic subtype, and muscarine (a toxin found in certain mushrooms) will bind preferentially to the muscarinic subtype. 

The acute form of diarrhea is short-lived and can be effectively prevented or rapidly suppressed by concomitant atropine. The cholinergic symptoms are accompanied by abdominal cramps (36%), sweating (57%), salivation (11%), visual disturbances (15%), lacrimation (12%), and piloerection (3%). The recommended dose of atropine is 0.25 mg intravenously for prevention or 0.25-1.0 mg for acute treatment of patients with early cholinergic symptoms. As cholinergic symptoms have not been observed with other camptothecin derivatives, it can be speculated that these adverse effects are restricted to irinotecan, whose piperidino group bears some structural similarity to the potent nicotine receptor stimulant dimethylphenylpiperazinium (106). 

Muscarine binds to the so-called muscarinic receptors in the parasympathetic nervous system. These are primarily postganglionic cholinergic receptors in smooth muscle and glands. Muscarine does not act on so-called nicotinic receptors, which are found in ganglionic synapses and at the neuromuscular junction. Muscarine is a tertiary amine structure and, therefore, does not diffuse into the central nervous system to an appreciable extent. Symptoms are, therefore, limited to the peripheral nervous system. 

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