Nicotinic acetylcholine receptors, or nAChRs, are ionotropic receptors that form ion channels in cells' plasma membranes. Like the other type of acetylcholine receptors, muscarinic acetylcholine receptors, their opening is triggered by the neurotransmitter acetylcholine, but they are also opened by nicotine (Siegel et al., 1999; Itier and Bertrand, 2001). Their action is inhibited by curare. Ionotropic receptor (also ligand gated ion channel) are a subclass of transmembrane receptors. ... Ion channels are present in the membranes that surround all biological cells. ... Cells in culture, stained for keratin (red) and DNA (green). ... Drawing of a cell membrane A component of every biological cell, the cell membrane (or plasma membrane) is a thin and structured bilayer of phospholipid and protein molecules that envelopes the cell. ... An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of the neurotransmitter acetylcholine. ... Muscarinic receptors are those membrane-bound acetylcholine receptors that are more sensitive to muscarine than to nicotine. ... Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a neuron and another cell. ... The chemical compound acetylcholine, often abbreviated as ACh, was the first neurotransmitter to be identified. ... Nicotine is an organic compound, a pyrrolidine-like alkaloid found naturally in the nightshade family of plants, such as tobacco and tomatoes. ... Strychnos toxifera by Koehler 1887 Curare is a substance containing the alkaloid D-tubocurarine. ...

Nicotinic acetylcholine receptors are present in many tissues in the body. The neuronal receptors are found in the central nervous system and the peripheral nervous system. The neuromuscular receptors are found in the neuromuscular junctions of somatic muscles; stimulation of these receptors causes muscular contraction. A diagram showing the CNS: 1. ... The peripheral nervous system or PNS, is part of the nervous system, and consists of the nerves and neurons that reside or extend outside the central nervous system--to serve the limbs and organs, for example. ...

Structure

Nicotinic receptors, with a molecular weight of about 280 kDa, are made up of five receptor subunits, arranged symmetrically around the central pore. They share similarities with GABA_A receptors, glycine receptors, and the type 3 serotonin receptors, which are all therefore classed into the nicotinicoid receptor family, or the signature Cys-loop proteins (Cascio, 2004). The atomic mass unit (amu), unified atomic mass unit (u), or dalton (Da), is a small unit of mass used to express atomic masses and molecular masses. ... The GABA-a pentameric receptor The GABAA receptor is one of the three ligand-gated ion channels responsible for mediating the effects of Gamma-AminoButyric Acid (GABA), the major inhibitory neurotransmitter in the human body. ... The Glycine receptor is one of the most widely distributed inhibitory receptors in the Central nervous system. ... In the field of neurochemistry, 5-HT receptors are receptors for the neurotransmitter and peripheral signal mediator serotonin, also known as 5-hydroxytryptamine or 5-HT. 5-HT receptors are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin...

Twelve types of nicotinic receptor subunits, α2 through 10 and β2 through 4 (Itier and Bertrand, 2001), combine to form pentamers. The subunits are somewhat similar to one another, especially in the hydrophobic regions (Siegel et al., 1999). The muscle form of the nAChR consist of two α subunits, a β, a δ and either a γ or an ε (Siegel et al., 1999; Itier and Bertrand, 2001; Giniatullin et al., 2005). The neuronal forms are much more heterogeneous, with a wide range of possible subunit combinations. In chemistry, hydrophobic or lipophilic species, or hydrophobes, tend to be electrically neutral and nonpolar, and thus prefer other neutral and nonpolar solvents or molecular environments. ...

The sites for binding ACh are on the outside of the α subunits near their N termini (Siegel et al., 1999). When the agonist binds, the α subunits become more similar to the other subunits, the channel becomes more symmetrical (Colquhoun and Sivilotti, 2004), and a pore with a diameter of about 0.65 nm opens (Siegel et al., 1999). The metre, or meter (symbol: m) is the SI base unit of length. ...

Opening the channel

Nicotinic AChRs may exist in different interconvertible conformational states. Binding of nicotine stabilizes the open and desensitised states. Opening of the channel allows positively charged ions, in particular, sodium and calcium, to enter the cell. Desensitization is a method to reduce or eliminate an organisms negative reaction to a substance or stimulus. ... It has been suggested that Negative atomic ion be merged into this article or section. ... General Name, Symbol, Number sodium, Na, 11 Chemical series alkali metals Group, Period, Block 1, 3, s Appearance silvery white Atomic mass 22. ... General Name, Symbol, Number calcium, Ca, 20 Chemical series alkaline earth metals Group, Period, Block 2, 4, s Appearance silvery white Atomic mass 40. ...

The nAChR is permeable to Na⁺ and K⁺, with some subunit combinations that are also permeable to Ca²⁺ (Siegel et al., 1999). The amount of sodium and potassium the channels allow through their pores (their conductance) is about 25 pS (Siegel et al., 1999), but the conductance depends on the actual subunit composition. Interestingly, because some neuronal nAChRs are permeable to Ca²⁺, they can affect the release of other neurotransmitters (Itier and Bertrand, 2001). The channel usually opens rapidly and tends to remain open until the agonist diffuses away, usually for about 1 millisecond (Siegel et al., 1999). However, AChRs can open sometimes with only one agonist bound and in rare cases with no agonist bound, and they can close spontaneously even when ACh is bound, so ACh binding only creates a probability of pore opening, which increases as more ACh binds (Colquhoun and Sivilotti, 2004). The siemens (symbol: S) is the SI derived unit of electric conductance. ... Agonists An agonist is a substance that binds to a receptor and triggers a response in the cell. ... Schematic drawing of the effects of diffusion through a semipermeable membrane. ... Mil-li-sec-ond One hundreth of a second ...

Effects

This activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movements of cations cause a depolarization of the plasma membrane, which results in an excitation, particularly of neurons, but also by the activation of other voltage-gated ion channels. On the other hand, the entry of calcium acts, either directly or indirectly, on different intracellular cascades leading, for example, to the regulation of the activity of some genes or the release of neurotransmitters. Neurons (also called nerve cells) are the primary cells of the nervous system. ... In biology, depolarization is the event a cell undergoes when its membrane potential grows more positive with respect to the extracellular solution. ... Drawing by Santiago Ramón y Cajal of cells in the pigeon cerebellum. ... Voltage-gated ion channel is a ion channel that is specifically activated, or gated, by the surrounding potential difference near the channel (or near the cell, neuron or synapse). ... A Biochemical Cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. ... This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ... Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a presynaptic and a postsynaptic neuron. ...

Roles

The subunits of the nicotinic receptors belong to a multigene family (16 members in human) and the assembly of combinations of subunits results in a large number of different receptors (For more information see the Ligand Gated Ion Channel database). These receptors, with highly variable kinetic, electrophysiological and pharmacological properties, respond differently to nicotine, at very different effective concentrations. This functional diversity allows them to take part in two major types of neurotransmission. Classical synaptic transmission (wiring transmission) involves the release of high concentrations of neurotransmitter, acting on immediately neighbouring receptors. In contrast, paracrine transmission (volume transmission) involves neurotransmitters released by synaptic buttons or varicosities, which then diffuse through the extra-cellular medium until they reach their receptors, which may be distant. Nicotinic receptors can also be found in different synaptic locations, for example the muscle nicotinic receptor always functions post-synaptically. The neuronal forms of the receptor can be found both post-synaptically (involved in classical neurotransmission) and pre-synaptically (where they can influence the release of other neurotranmsitters). Kinetic energy (also called vis viva, or living force) is energy possessed by a body by virtue of its motion. ... Electrophysiology is the study of the electrical properties of biological cells and tissues. ... Pharmacology (in Greek: pharmacon (φάρμακον) meaning drug, and logos (λόγος) meaning science) is the study of how chemical substances interact with living systems. ... Nicotine is an organic compound, a pyrrolidine-like alkaloid found naturally in the nightshade family of plants, such as tobacco and tomatoes. ... Synapses allow nerve cells to communicate with one another through axons and dendrites, converting electrical signals into chemical ones. ... Paracrine signalling is a form of signalling in which the target cell is close to the signal releasing cell, and the signal chemical is broken down too quickly to be carried to other parts of the body. ... Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a presynaptic and a postsynaptic neuron. ... Synapses allow nerve cells to communicate with one another through axons and dendrites, converting electrical signals into chemical ones. ...

Subtypes

The two main receptor subtypes are the neuromuscular receptors and the neuronal (ganglionic) receptors. The neuronal receptors are found in the central nervous system and on all autonomic ganglia. The neuromuscular receptors are found in the neuromuscular junctions of somatic muscles. Stimulation of these receptors causes muscular contraction. A diagram showing the CNS: 1. ... Sympathetic nervous system innervation, showing the sympathetic chain ganglia An autonomic ganglion is a collection of neuron cell bodies within the autonomic nervous system. ...

References

1. Cascio, M. 2004. Structure and function of the glycine receptor and related nicotinicoid receptors. Journal of Biological Chemistry, 279(19), 19383-19386. Available.
2. Colquhoun D. and Sivilotti L.G. 2004. Function and structure in glycine receptors and some of their relatives. Trends in Neurosciences, 27(6), 337-344.
3. Giniatullin R., Nistri A., and Yakel J.L. 2005. Desensitization of nicotinic ACh receptors: shaping cholinergic signaling. Trends in Neurosciences, 28(7), 371-378.
4. Itier V. and Bertrand D. 2001. Neuronal nicotinic receptors: from protein structure to function. Edited by Andreas Engel and Giorgio Semenza. FEBS Letters, 504(3), 118-125.
5. Siegel G.J., Agranoff B.W., Fisher S.K., Albers R.W., and Uhler M.D. 1999. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Sixth Edition. GABA Receptor Physiology and Pharmacology. American Society for Neurochemistry. Lippincott Williams and Wilkins. Available.