ACH receptor

The neurotransmitter acetylcholine (ACh) exerts its diverse pharmacological actions via binding to and subsequent activation of two general classes of cell surface receptors, the nicotinic and the mAChRs. These two classes of ACh receptors have distinct structural and functional properties. The nicotinic receptors,... 

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. 

FIGURE 43-2 Photomicrograph of the human neuromuscular junction. In normal muscle, Ach receptors are associated with the terminal expansions of the junctional folds and the architecture of the postjunctional membrane follows closely the distribution of active zones in the presynaptic membrane, b, basal lamina I, infoldings m, mitochondria M, myocyte N, nerve terminal r, ribosomes s, synaptic space S, Schwann cell. Courtesy of A. Engel. 

ARIA ACh receptor-inducing activity CICR Ca2+-induced Ca2+ release... 

Vesicle You should demonstrate that there are two stores of acetylcholine (ACh), one deep in the nerve terminal and one clustered beneath the surface opposite the ACh receptors in the so-called active zones . The deep stores serve as a reserve of ACh while those in the active zones are required for immediate release of ACh into the synaptic cleft. 

ACh receptor These are located on the peaks of the junctional folds of the muscle membrane as shown. They are also found presynaptically on the nerve terminal, where, once activated, they promote migration of ACh vesicles from deep to superficial stores. 

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. 

Nishizaki T, Morales A, Gehle VM, Sumikawa K. 1994. Differential interactions of gentamicin with mouse junctional and extrajunctional ACh receptors e3q>ressed in Xenopus oocytes. Brain Res Mol Brain Res 21 (1-2) 99. 

Sumikawa K, Houghton M, Emtage JS, Richards BM, Barnard FA. 1981. Active multi-subunit ACh receptor assembled by translation of heterologous mRNA in Xenopus oocytes. 

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... 

Sudweeks SN, Yakel JL (2000) Functional and molecular characterization of neuronal ACh receptors in rat CAl hippocampal neurons. J Physiol 527 515-528... 

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... 

Typical Blocks ACh receptor U Histamine Psychotic disorders... 

In skeletal muscle fibers whose motor nerve has been severed, ACh receptors spread in a few days over the entire cell membrane. In this case, succinylcholine would evoke a persistent depolarization with contracture and hyperkalemia. These effects are likely to occur in polytraumatized patients undergoing follow-up surgery. 

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. 

The muscarinic ACh receptors (of which there are at least five subtypes) are metabotropic. Their name is derived from the alkaloid muscarine, which is found in the fly agaric mushroom (Amanita muscaria), for example. Like ACh, muscarine is bound at the receptor, but in contrast to ACh (see C), it is not broken down and therefore causes permanent stimulation of muscle. 

The muscarinic ACh receptors influence the cAMP level in the postsynaptic cells (Mi, M3 and Ms increase it, while subtypes M2 and M4 reduce it). 

Ach + receptor Na influx action potential increased free Ca contraction... 

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. 

Anticholinesterase agents of all classes can initiate antidromic firing of action potentials in motor neurons, possibly due to an activation of prejunctional ACh receptors that are activated by the elevated synaptic ACh. Quaternary ammonium inhibitors can also act as agonists at these receptors. The initiation of antidromic firing may be a mechanism by which cholinesterase inhibitors produce fasciculation of skeletal muscle. 

ACh diffusing across the synaptic cleft may bind to ACh receptors (AChRs) to produce an electrical response, interact with acetylcholinesterase (AChE) and be hydrolyzed, or diffuse into the systemic circulation. 

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. 

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