Nicotinic Ach receptor

Autonomic nervous system (A, middle). In analogy to autonomic ganglia, NAChR are found also on epinephrine-releasing cells of the adrenal medulla, which are innervated by spinal first neurons. At all these synapses, the receptor is located postsynaptically in the somatodendritic region of the gangliocyte. 

Motor end plate. Here the ACh receptors are of the motor type (p.182). 

Central nervous system (CNS A, top). NAChR are involved in various functions. They have a predominantly presynaptic location and promote transmitter release from innervated axon terminals by means of depolarization. Together with ganglionic NAChR they belong to the neuronal type, which differs from the motor type in terms of the composition of its five subunits. 

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Wannacott, S (1997) Presynaptic nicotinic ACh receptors. Trends Neurosci. 20 92-98. 

Desensitization can be defined as the tendency of a response to wane, despite the presence of a stimulus of constant intensity (e.g., constant agonist concentration). In the case of the nicotinic ACh receptor, good evidence suggests that desensitization results from a change in receptor conformation to an inactive refractory state (Rang and Ritter, 1970). To describe this in terms of the AChR activation mechanism, we could add a desensitized state to the scheme shown in Eq. (6.2) to give ... 

The postsynaptic membrane opposite release sites is also highly specialized, consisting of folds of plasma membrane containing a high density of nicotinic ACh receptors (nAChRs). Basal lamina matrix proteins are important for the formation and maintenance of the NMJ and are concentrated in the cleft. Acetylcholinesterase (AChE), an enzyme that hydrolyzes ACh to acetate and choline to inactivate the neurotransmitter, is associated with the basal lamina (see Ch. 11). 

ACh was first proposed as a mediator of cellular function by Hunt in 1907, and in 1914 Dale [2] pointed out that its action closely mimicked the response of parasympathetic nerve stimulation (see Ch. 10). Loewi, in 1921, provided clear evidence for ACh release by nerve stimulation. Separate receptors that explained the variety of actions of ACh became apparent in Dale s early experiments [2]. The nicotinic ACh receptor was the first transmitter receptor to be purified and to have its primary structure determined [3, 4]. The primary structures of most subtypes of both nicotinic and muscarinic receptors, the cholinesterases (ChE), choline acetyltransferase (ChAT), the choline and ACh transporters have been ascertained. Three-dimensional structures for several of these proteins or surrogates within the same protein family are also known. 

Finally, a thorough receptor binding study by Raffa and colleagues (1998) showed that hypericin extracts had no effect at adrenergic (alpha or beta), adenosine, angiotensin, benzodiazepine, dopamine, bradykinin, neuropeptide Y, PCP, NMDA, opioid, cholecystokinin A, histamine HI, or nicotinic ACh receptors. Although comprehensive, this study did not look at the binding of any other hypericum constituents. 

Keyser KT, Britto ERG, Schoepfer R, Whiting P Cooper J, Conroy W, Brozozowska-Prechtl A, Karten HJ, Lindstrom J (1993) Three subtypes of a-bungarotoxin-sensitive nicotinic acetylcholine receptors are expressed in chick brain. J Neurosci 13 442-452 Khiroug S, Harkness PC, Lamb PW, Sudweeks S, Khiroug L, Millar NS, Yakel JL (2002) Rat nicotinic ACh receptor al and fil subunits co-assemble to form functional heteromeric nicotinic receptor channels. J Physiol 540 425 34... 

Wonnacott S (1997) Presynaptic nicotinic ACh receptors. Trends Neurosci 20 92-98 Wonnacott S, Mogg A, Bradly A, Jones IW (2002) Presynaptic nicotinic acetylcholine receptors subtypes mediating neurotransmitter release. In Levin ED (ed) Nicotine and the nervous system. CRC, Boca Raton, pp 29-50... 

The nicotinic ACh receptor responds to the alkaloid nicotine contained in tobacco (many of the physiological effects of nicotine are based on this). The nicotinic receptor is ionotropic. Its properties are discussed in greater detail on p. 222. 

All muscarinic receptors are members of the seven transmembrane domain, G protein-coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic receptors by an agonist triggers the release of an intracellular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus even-numbered receptor subtypes can be conveniently distinguished. Activation of Ml, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated release of intracellular calcium, the release of diacylglyc-erol (which can activate protein kinase C), and stimulation of adenylyl cyclase. These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle. 

Nicotinic ACh receptor (AChR) at the muscle end plate. A. The AChR is a pentameric complex made up of five subunits surrounding a central conducting channel. Embryonic AChR, containing the 7-subunit as shown, is a low-conducting channel. Adult AChR has instead an e-subunit and is a high-conducting channel. 

The process of neuromuscular transmission includes the synthesis and storage of acetylcholine (ACh), its release and passage across the synaptic cleft, the interaction with nicotinic ACh receptor, and the process of actual muscle contraction. 

ACh receptors are present in the post-junctional membrane of the endplate, in the junctional folds. The nicotinic ACh receptor at the motor endplate has five subunits, two os, (3, 5 and . In addition, a Y subunit instead of an e subunit may be present in the so-called extra-junctional or the fetal receptor. The five subunits are arranged as a cylinder around a central funnel-shaped pore, the ion channel. The two a subunits each carry a recognition site which binds nicotinic agonists such as ACh and antagonists such as the neuromuscular blocking agents. Whilst ACh must bind to both subunits to produce an effect, it is sufficient for... 

Analysis of the cholinergic effects of galanthamine in a mouse model suggests that galanthamine does not affect choline acetyltransferase, the choline carrier, or agonist binding to the active site of either muscarinic or nicotinic ACh receptors. 

Verhage M, Maia AS, Plomp JJ, Brussaard AB, Heeroma JH, et al. (2000) Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287 864—9 Wonnacott S (1997) Presynaptic nicotinic ACh receptors. Trends Neurosd 20 92-8 Weber T, Zemelman BV, McNew JA, Westermann B, Gmachl M, Parlati F, Sollner TH, Rothman JE (1998) SNAREpins minimal machinery for membrane fusion. Cell 92 759-72 Whittaker VP, Sheridan MN (1965) The morphology and acetylcholine content of isolated cerebral cortical synaptic vesicles. J Neurochem 12 363-72 Xu J, Mashimo T, Siidhof TC (2007) Synaptotagmin-1, -2, and -9 Ca2+ sensors for fast release that spedfy distinct presynaptic properties in subsets of neurons. Neuron 54 567-81 Zucker RS, Regehr WG (2002) Short-term synaptic plasticity. Annu Rev Physiol 64 355 405... 

Nicotinic receptor. [3H]-Nicotine (85 Ci/mmol Amersham) was used to assay specific binding of alkaloids to the nicotinic ACh receptor (nAChR). The membrane preparation was incubated for 40 min with differing concentrations of alkaloids or 1 mM nicotine as a positive control. The GF/C filters were presoaked with polyethylene glycol 8000 (5% in water) for 3 h to reduce nonspecific binding of [3H]-nicotine. Further procedures were the same as described above for mAChR. 

The total synthesis of homoanatoxin-a, as an analog of anatoxin-a, was also accomplished in 1992 [33]. It is a potent nicotinic agonist active at the postsynaptic nicotinic ACh receptor channel complex [54]. Although not as potent as anatoxin-a, homoanatoxin-a has provided valuable insight for SAR studies of anatoxin-a and its homologs. 

Jones IW, Wonnacott S (2005) Why doesn t nicotinic ACh receptor immunoreactivity knock out ... 

Tozaki H, Matsumoto A, Karmo T, Nagai K, Nagata T, Yamamoto S, Nishizaki T (2002) The inhibitory and facilitatoty actions of amyloid-beta peptides on nicotinic ACh receptors and AMPA receptors. Biochem Biophys Res Common 294 42-45... 

Nerve agents are OP compounds, which irreversibly inhibit AChE, leading to ACh accumulation, and cause over-stimulation of muscarinic and nicotinic ACh receptors. The effect at the SA node, the primary heart control site, is inhibitory and bradycardia results. VX primarily affects neurotransmitter receptors, those of norepinephrine, and also affects the central nervous system (CNS) not related to AChE inhibition. 

Sarin was involved in terrorist attacks in Japan (Okumura et al, 2003 Okudera, 2002). The increase in sympathetic and parasympathetic tone results in tachycardia, ST-segment modulation (Abraham et al, 2001), and arrhythmia. Inhibition of cholinesterase within the neuroeffector junction also affects nerve impulse transmission by direct action. Direct action on muscarinic or nicotinic ACh receptors (Somani et al, 1992) is observed when the blood level of sarin exceeds the micromolar level. Sarin inhibits RBC-AChE 80-100% as well as plasma-BChE between 30 and 50% (Grob and Harvey, 1958). It also binds to aliesterase, an enzyme that contributes to ester-link hydrolysis. 

The standard treatment of nerve agent-induced muscle toxicity calls for (1) reactivation of the phosphorylated AChE with an oxime, and (2) blockage of the nicotinic ACh receptor sites from the stimulating action of ACh with fii-tubocurarine. Oximes such as obidoxime, pralidoxime (2-pyridine aldoxime methochloride, 2-PAM) and a few others have been found very effective when given in combination with other drugs such as atropine, pretreatment with oximes varies with the ehemieal structures of the nerve agents and depends on the time after exposure. For example, it has been... 

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