Nicotinic Acetylcholine - Essay Example

Nicotinic Acetylcholine One of the key molecules involved in the propagation of signals between neurons and their targets in the central nervous system and peripheral synapses is nicotinic acetylcholine receptor (nAChR). As a typical example of the ligand-gated ion channels super family, nicotinic acetylcholine receptor is a member of the Cys-loop family. Cys-loop family includes the 5-hydroxytryptamine type 3 (5-HT3) receptor, -aminobutyric acid type A (GABAA) and GABAC receptors, and glycine (inhibitory) receptors. (Colquhoun 2007) These receptors are ionotropic receptors that form ligand-gated ion channels in the plasma membrane. Synthesized in the endoplasmic reticulum, a fraction of the subunits of this receptor assemble into homo and hetero-pentameric complexes. The only complexes that reach the cell surface, after exiting from endoplasmic reticulum are the pentameric complexes. nAChRs have been identified as crucial elements in central nervous system functions such as consciousness, attention, and memory; and participate in numerous cerebral circuits. (Bocquet, Carvalho, Cartaud, Neyton Poupon, Taly, Grutter, Changeux, Corringer 2007) The opening of the channels of these receptors is triggered by the neurotransmitter acetylcholine. Nicotine also has the same effect. A diagram of the chemical structure of acetylcholine is given below. Acetylcholine Nicotinic acetylcholine receptors are located mainly in the postsynaptic membrane under the motor nerve terminal at the neuromuscular junction. Nicotinic receptors can also be found in different synaptic locations; e.g. the muscle nicotinic receptor always functions post-synaptically. The nerve cell forms of the receptor can be found both post-synaptically (performing classical neurotransmission) and pre-synaptically (causing the release of other neurotransmitters). In contrast to the muscarinic acetylcholine receptors, Nicotinic Acetylcholine receptors do not operate with the help of a second messenger. Instead they open themselves forming an ion channel. Curare causes inhibition of these receptors. Nicotinic acetylcholine receptors have a very wide distribution in the various body tissues. Nerve cell receptors are found in the central nervous system and also in the peripheral nervous system. The neuromuscular receptors, on the other hand are found in the neuromuscular junctions of somatic muscles. The stimulation of these receptors causes muscular contraction.(Barrantes 1998) Structure and function of Nicotinic Acetylcholine Receptors The nicotinic acetylcholine receptor protein includes one or many sites which can bind the neurotransmitter ACh and also a specific channel for cat ions which is also known as the intrinsic cationic channel. These ions can be Na+, Ca2+ or K+ and the channel is specific in nature. The process of the opening of ion channel is linked to the binding of ACh. (Maelicke 1986) Protein chemistry and sequence analysis of polypeptide has revealed a general scheme for each subunit which consists of : 1. A globular extra cellular N-terminal domain (ECD); 2. A trans-membrane domain (TMD) 3. A cytoplasmic domain There are 2 to 5 Acetylcholine binding sites on the ECD. Nicotinic receptors have many subunits and these subunits belong There are 2 to 5 Acetylcholine binding sites on the ECD. Nicotinic receptors have many subunits and these subunits fit in a multigene family (seventeen members in the human being) When many of the subunits combine they form a great numbers of receptors. Every subunit gives three parts or "loops" to the site of binding. The sites which bind ACh are located on the outer side of the subunits. And as the agonist binds, the subunits happen to be more alike to the other subunits. And the channel gets more proportioned and a hole of about 0.65nm in diameter opens up. This channel helps the nicotinic acetylcholine receptor to adhere to its role by many ways. Firstly it encloses a mechanism of gating which is closed in the inactive states of the channel but it is open in the active states. It includes a water pore that helps to steady out the movement of ions inside the hydrophobic atmosphere of the cell. Thirdly it contains a partially permeable filter which helps to choose ions related to their charges. The receptors activated by nicotine alter the condition of neurons by two major processes. Firstly the activity of cat ions source a situation which depolarizes the cell membrane which further gives an excitation to the neurons in particular. Secondly the entrance of calcium acts on dissimilar intracellular flow leading. Development of Novel Drugs Currently available smoking cessation therapies have limited success rates. At the moment, a total of nearly 35 drug candidates are in pipeline, for the treatment of alcohol, narcotic and nicotine dependence. Approaches which are under investigation include the use of cannaboid-1 receptor antagonists (rimonabant), inhibitors of the hepatic P-450 enzyme (methoxsalen), , nicotine vaccines and partial nicotine agonists. (Brody, Mandelkern, London, Olmstead, Farahi, Scheibal, Jou, Allen, Tiongson, Chefer 2006) New and more efficacious drugs are being developed as a result of the improved understanding of the structure and function of nAChR. Addiction's secret lie in how these drug molecules stimulate the "Reward pathway" of the nervous system. The circuitry for this pathway seems to be located in the Limbic System of the brain, and is believed to work by the release of Dopamine. (Hauser, Jordan, Gatto 2006) Nicotine replacement and/or bupropion are considered first-line therapies, whereas, clonidine and nortriptyline as second-line treatments. Treatments with less proven efficacy include bromocriptine, antianxiety drugs, monoamine oxidase inhibitors, opioid receptor antagonists, selective serotonin reuptake inhibitors, nicotinic receptor antagonists (e.g., mecamylamine), and glucose tablets. (Hong 2004) Nicotine replacement therapies (NRTs) include patches, gums, lozenges, nasal sprays, and inhalers for delivering controlled doses of the addictive drug itself. NRTs ease withdrawal symptoms but neither do they help control neurotransmitter release nor do they blunt the addictive effects of nicotine. Zyban (bupropion hydrochloride), which was approved by FDA in May 1997, has one thing that makes it different from other drugs and that is, it contains no nicotine. Cytisine is an agonist of the nicotinic acetylcholine receptor, and is available for the treatment of tobacco smoking. Pharmacologically it has effects similar to nicotine, which is due to its structural similarity. A Cystisine derivative, non-nicotinic treatment that has emerged is varenicline. Varenicline is well tolerated and may provide a novel therapy to aid smoking cessation. Varenicline which is a partial agonist works through the same nicotinic receptor population that is used by substances of abuse. Scientific studies have shown that nicotine targets nAChRs, which are located in a region of the brain thought to be very central to the process of reward and habituation. (Parrington Coward 2007) Bibliography COLQUHOUN, D. (2007). Nicotinic Acetylcholine Receptors From Molecular Biology to Cognition J.-P. 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