Acetylcholine

Nicotine

File:Acetylcholine receptor.png Acetylcholine receptor (nicotinic) from electric torpedo rays (very similar to human receptor) is made of 5 subunits, 2 of which (shown in orange) bind ACh (red). Structure was determined by electron crystallography at 4 Å resolution (PDB code: 2bg9) (more details...)

Acetylcholine 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 cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons. Being ionotropic receptors, nAChRs are directly linked to an ion channel and do not make use of a second messenger as metabotropic receptors do.^[1]

Like the other type of acetylcholine receptors - muscarinic acetylcholine receptors (mAChRs) - the nAChR is triggered by the binding of the neurotransmitter acetylcholine (ACh). However, whereas muscarinic receptors are also activated by muscarine, nicotinic receptors are also opened by nicotine. Hence, the name "nicotinic".^[2][3][1]

Nicotinic acetylcholine receptors are present in many tissues in the body and are the best-studied of the ionotropic receptors.^[1] 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.

[edit] Structure

Nicotinic receptors, with a molecular mass of 290 kDa^[4], are made up of five subunits, arranged symmetrically around a central pore.^[1] They share similarities with GABA_A receptors, glycine receptors, and the type 3 serotonin receptors (which are all ionotropic receptors), or the signature Cys-loop proteins.^[5]

Nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression: muscle type and neuronal type. In the muscle type, found at the neuromuscular junction, receptors are either the embryonic form, composed of α1, β1, δ, and γ 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.^[2][3][6][1] The neuronal subtypes are various homomeric or heteromeric combinations of twelve different nicotinic receptor subunits: α2 through α10 and β2 through β4. Examples of the neuronal subtypes include: (α4)₃(β2)₂, (α4)₂(β2)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. The neuronal forms differ from the muscle forms in that they are not sensitive to α-bungarotoxin.^[1]

[edit] Binding the channel

Like 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 including: ligand. In addition to the endogenous agonist, acetylcholine, examples of agonists of the nAChR are: nicotine, epibatidine, and choline.

In neuronal nAChRs, the acetylcholine binding site is formed from amino acid residues of both the α and β subunits (or between two α subunits in the case of homomeric receptors) in the extracellular domain near the N terminus.^[2] When an agonist binds to the site, all present subunits undergo a conformational change and the channel is opened ^[7] and a pore with a diameter of about 0.65 nm opens.^[2]

[edit] Opening the channel

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] 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.^[8]

Interestingly, 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 only creates a probability of pore opening, which increases as more ACh binds.^[7]

[edit] 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 depolarisation of the plasma membrane (which results in an excitatory postsynaptic potential in 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.

[edit] Receptor regulation

[edit] Receptor desensitisation

Ligand-bound desensitisation of receptors was first characterised by Katz and Thesleff in the nicotinic acetylcholine receptor.^[9]

Prolonged or repeat exposure to a stimulus often results in decreased responsiveness of that receptor toward a stimulus, termed desensitisation (for example: myasthenia gravis). nAChR function can be modulated by phosphorylation^[10] by the activation of second messenger-dependent protein kinases. PKA^[9] and PKC^[11] 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.^[12] This receptor desensitisation has been previously modeled in the context of a two-state mathematical model (see this link [1]) Desensitised receptors can revert back to a prolonged open state when an agonist is bound in the presence of a positive allosteric modulator, for example PNU-120596 ^[13].

[edit] Roles

The subunits of the nicotinic receptors belong to a multigene family (17 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 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 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 ^[14] where they can influence the release of multiple neurotransmitters.

[edit] 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.^[15]

The nAChR subunits have been divided into 4 subfamilies (I-IV) based on similarities in protein sequence.^[16] In addition, subfamily III has been further divided into 3 tribes.

• Alpha genes: CHRNA1 (muscle), CHRNA2 (neuronal), CHRNA3, CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNA8, CHRNA9, CHRNA10
• Beta genes: CHRNB1 (muscle), CHRNB2 (neuronal), CHRNB3, CHRNB4,
• Other genes: CHRND (delta), CHRNE (epsilon), CHRNG (gamma)

[edit] Notable variations

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, specifically (α1)₂β1δε (muscle type), (α3)₂(β4)₃ (ganglion type), (α4)₂(β2)₃ (CNS type) and (α7)₅ (another CNS type).^[17] A comparison follows:

[edit] See also

• Drug Discovery and Development: Nicotinic Acetylcholine Receptor Agonists

[edit] References

[edit] External links

Wikiversity has learning materials about Poisson–Boltzmann profile for an ion channel

• Calculated spatial position of Nicotinic acetylcholine receptor in the lipid bilayer