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Nicotinic antagonists

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Nicotinic antagonists

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Acetylcholine Acetylcholine

Nicotine Nicotine

Acethylcholine receptor (nicotinic) from electric torpedo rays (very similar to human receptor) is made of 5 subunit, 2 of which (shown in orange) binds to ACh (red) (PDB code: 2bg9) (more details...) Acethylcholine receptor (nicotinic) from electric torpedo rays (very similar to human receptor) is made of 5 subunit, 2 of which (shown in orange) binds to ACh (red) (PDB code: 2bg9) (more details...)

Acethylcholine receptor blocked by cobra venom (PDB code: 1yi5). A similar effect can be achieved by high doses of curare or nicotine (more details...) Acethylcholine receptor blocked by cobra venom (PDB code: 1yi5). A similar effect can be achieved by high doses of curare or nicotine (more details...)

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.

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.

Contents

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 GABAA 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).

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.

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).

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.

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).

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.

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).

Subunits

To date 17 nAChR subunits have been identified, these are divided into muscle-type and neuronal-type subunits. Of these 17 subunits, α2-α7 and β2-β4 have been cloned in humans, the remaining genes identified in chick and rat genomes (Graham et al. 2002). The nAChR subunits have been divided into 4 subfamilies (I-IV) based on similarities in protein sequence. In addition, subfamily III has been further divided into 3 tribes.

Neuronal-type Muscle-type
I II III IV
α9, α10 α7, α8 1 2 3 α1, β1, δ, γ, ε
α2, α3, α4, α6 β2, β4 β3, α5

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.
  6. Graham A., Court J.A., Martin-Ruiz C.M., Jaros E., Perry R., Volsen S.G., Bose S., Evans N., Ince P., Kuryatov A., Lindstrom J., Gotti C., and Perry E.K. 2002. Immunohistochemical localisation of nicotinic acetylcholine receptor subunits in human cerebellum. Neuroscience, 113(3), 493-507.

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