Nicotinic acetylcholine receptor

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Nicotinic acetylcholine receptors, or nAChRs, are neuron receptor proteins that signal for muscular contraction upon a chemical stimulus. They are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the presynaptic and postsynaptic sides of the neuromuscular junction. Like ionotropic receptors, nAChRs are directly linked to ion channels and do not use second messengers (as metabotropic receptors do). Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors.[1]

Like the other type of acetylcholine receptor—the muscarinic acetylcholine receptor (mAChR)—the nAChR is triggered by the binding of the neurotransmitter acetylcholine (ACh). Just as muscarinic receptors are named such because they are also activated by muscarine, nicotinic receptors can be opened not only by acetylcholine but also by nicotine —hence the name "nicotinic."[1][2][3]

In insects, the cholinergic system is limited to the central nervous system.[4] In contrast, neuronal receptors are found in both the central nervous system and the peripheral nervous system of mammals. Mammalian neuromuscular receptors are found in the neuromuscular junctions of somatic muscles.

Structure[edit]

Nicotinic receptors, with a molecular mass of 290 kDa,[5] are made up of five subunits, arranged symmetrically around a central pore.[1] Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. They possess similarities with GABAA receptors, glycine receptors, and the type 3 serotonin receptors (which are all ionotropic receptors), or the signature Cys-loop proteins.[6]

In vertebrates, nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression: muscle-type nicotinic receptors and neuronal-type nicotinic receptors. In the muscle-type receptors, found at the neuromuscular junction, receptors are either the embryonic form, composed of α1, β1, γ, and δ subunits in a 2:1:1:1 ratio, or the adult form composed of α1, β1, δ, and ε subunits in a 2:1:1:1 ratio.[1][2][3][7] The neuronal subtypes are various homomeric or heteromeric combinations of twelve different nicotinic receptor subunits: α2−α10 and β2−β4. Examples of the neuronal subtypes include: (α4)32)2, (α4)22)3, and (α7)5. In both muscle-type and neuronal-type receptors, the subunits are somewhat similar to one another, especially in the hydrophobic regions.

Binding the channel[edit]

As with all ligand-gated ion channels, opening of the nAChR channel pore requires the binding of a chemical messenger. Several different terms are used to refer to the molecules that bind receptors, such as ligand. As well as the endogenous agonist acetylcholine, agonists of the nAChR are nicotine, epibatidine, and choline.

In muscle-type nAChRs, the acetylcholine binding sites are located at the α and either ε or δ subunits interface (or between two α subunits in the case of homomeric receptors) in the extracellular domain near the N terminus.[2][8] When an agonist binds to the site, all present subunits undergo a conformational change and the channel is opened[9] and a pore with a diameter of about 0.65 nm opens.[2]

Opening the channel[edit]

Nicotinic AChRs may exist in different interconvertible conformational states. Binding of an agonist stabilises the open and desensitised states. Opening of the channel allows positively charged ions to move across it; in particular, sodium enters the cell and potassium exits. The net flow of positively-charged ions is inward.

The nAChR is a non-selective cation channel, meaning that several different positively charged ions can cross through.[1] It is permeable to Na+ and K+, with some subunit combinations that are also permeable to Ca2+.[2][10][11] The amount of sodium and potassium the channels allow through their pores (their conductance) varies from 50–110 pS, with the conductance depending on the specific subunit composition as well as the permeant ion.[12]

It is interesting to note that, because some neuronal nAChRs are permeable to Ca2+, they can affect the release of other neurotransmitters.[3] The channel usually opens rapidly and tends to remain open until the agonist diffuses away, which usually takes about 1 millisecond.[2] However, AChRs can sometimes open with only one agonist bound and, in rare cases, with no agonist bound, and they can close spontaneously even when ACh is bound. Therefore, ACh binding creates only a probability of pore opening, which increases as more ACh binds.[9]

The nAChR is unable to bind ACh when bound to any of the snake venom α-neurotoxins. These α-neurotoxins antagonistically bind tightly and noncovalently to nAChRs of skeletal muscles, thereby blocking the action of ACh at the postsynaptic membrane, inhibiting ion flow and leading to paralysis and death. The nAChR contains two binding sites for snake venom neurotoxins. Progress towards discovering the dynamics of binding action of these sites has proved difficult, although recent studies using normal mode dynamics[13] have aided in predicting the nature of both the binding mechanisms of snake toxins and of ACh to nAChRs. These studies have shown that a twist-like motion caused by ACh binding is likely responsible for pore opening, and that one or two molecules of α-bungarotoxin (or other long-chain α-neurotoxin) suffice to halt this motion. The toxins seem to lock together neighboring receptor subunits, inhibiting the twist and therefore, the opening motion.[14]

Effects[edit]

The activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movement of cations causes a depolarization of the plasma membrane (which results in an excitatory postsynaptic potential in neurons), but also by the activation of 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.

Receptor regulation[edit]

Receptor desensitisation[edit]

Ligand-bound desensitisation of receptors was first characterised by Katz and Thesleff in the nicotinic acetylcholine receptor.[15]

Prolonged or repeat exposure to a stimulus often results in decreased responsiveness of that receptor toward a stimulus, termed desensitisation. nAChR function can be modulated by phosphorylation[16] by the activation of second messenger-dependent protein kinases. PKA[15] and PKC[17] have been shown to phosphorylate the nAChR resulting in its desensitisation. It has been reported that, after prolonged receptor exposure to the agonist, the agonist itself causes an agonist-induced conformational change in the receptor, resulting in receptor desensitisation.[18] This receptor desensitisation has been previously modeled in the context of a two-state mathematical model (see this link [1]) Desensitised receptors can revert to a prolonged open state when an agonist is bound in the presence of a positive allosteric modulator, for example PNU-120596.[19]

Roles[edit]

The subunits of the nicotinic receptors belong to a multigene family (16 members in humans) 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 to nicotine differently, 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 neighboring receptors. In contrast, paracrine transmission (volume transmission) involves neurotransmitters released by synaptic buttons, 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[20] where they can influence the release of multiple neurotransmitters.

Subunits[edit]

To date, 17 nAChR subunits have been identified, which 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.[21]

The nAChR subunits have been divided into 4 subfamilies (I-IV) based on similarities in protein sequence.[22] 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

Notable variations[edit]

Nicotinic receptors are pentamers of these subunits; i.e., each receptor contains five subunits. Thus, there is an immense potential of variation of the aforementioned subunits. However, some of them are more notable than others, to be specific, (α1)2β1δε (muscle-type), (α3)24)3 (ganglion-type), (α4)22)3 (CNS-type) and (α7)5 (another CNS-type).[23] A comparison follows:

Receptor-type Location Effect; functions Nicotinic agonists Nicotinic antagonists
Muscle-type:
1)2β1δε[23]
or
1)2β1δγ
Neuromuscular junction EPSP, mainly by increased Na+ and K+ permeability
Ganglion-type:
3)24)3
autonomic ganglia EPSP, mainly by increased Na+ and K+ permeability
Heteromeric CNS-type:
4)22)3
Brain Post- and presynaptic excitation,[23] mainly by increased Na+ and K+ permeability. Major subtype involved in the rewarding effects of nicotine.[25]
Further CNS-type:
3)24)3
Brain Post- and presynaptic excitation
Homomeric CNS-type:
7)5
Brain Post- and presynaptic excitation,[23] mainly by increased Ca2+ permeability. Major subtype involved in the pro-cognitive effects of nicotine.[26] Also involved in the pro-angiogenic effects of nicotine and accelerate the progression of chronic kidney disease in smokers.[27][28]

See also[edit]

References[edit]

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  14. ^ Samson, A. O.; Levitt, M. (2008). "Inhibition Mechanism of the Acetylcholine Receptor by α-Neurotoxins as Revealed by Normal-Mode Dynamics". Biochemistry 47 (13): 4065–4070. doi:10.1021/bi702272j. PMC 2750825. PMID 18327915.  edit
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External links[edit]