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ACETYLCHOLINE RECEPTOR

Nicotinic Acetylcholine Receptor (nAChRs) is a neurotransmitter receptor also known as a specialized integral membrane protein. Integral membrane proteins are permanently bound to the phospholipid bilayer. They provide a communication pathway between the internal and external environments of the cell. Acetylcholine receptor proteins reside as ligand-gated ion channels on the motor end plate of the postsynaptic cleft in the neuromuscular junction.

nAChRs as an ionotropic receptor, which are in direct facilitation of ion movement. When a ligand binds to the active site of the receptor, the channel responds by opening. Likewise, when the ligand is removed the channel closes. They are activated by the binding of the acetylcholine neurotransmitter. Once the receptor is activated the ion channel opens allowing the exchange of salt ions. Nicotinic acetylcholine receptors are responsible for the regulation of sodium (Na+) ion concentration entering and potassium (K+) ion concentration leaving the muscular cytosol, ultimately resulting in an action potential from the differences in electrochemical gradients.

Acetylcholine receptor proteins are present in the peripheral nervous system (PNS) as well as the central nervous system (CNS) in humans and many organisms, including invertebrates. The function of the receptor follows a general mechanism to which it is applied to almost any organism with a nervous system, that relies on the firing action potentials of the neurons. The structure depicted to the right is a redering of the the nicotinic acetylcholine receptor extracted from Torpedo marmorata, more commonly known as the Marbled Electric Ray. Specifically, it is extracted from the electric organ's tissue from within the organism.

Mechanism

The neurotransmitter acetylcholine binds specifically to the α-subunits in the homeric receptor example.

Structure

Nicotinic Acetylcholine Receptor is composed up five distinct subunits (shown in figure to left): α1, α2, β1, δ, and ε at approximately a molecular mass of 290 kDa. The subunits are symmetrically arranged around a central pore. Each subunit is a transmembrane domain with the N-terminus and C-terminus located on the extracellular side of the plasma membrane. Each subunit are composed of long protein chains that extend across the cell membrane. The subunits have a composition of around ~20% beta sheets and ~40% alpha helices from about ~370 residues in total.

In vertebrates, nicotinic receptors are classified by their main sites of expression into two subtypes: 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, 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. The neuronal subtypes are various combinations of twelve different nicotinic receptor subunits: α2 through α10 and β2 through β4. In both muscle-type and neuronal-type receptors, the subunits are somewhat similar to one another, especially in the hydrophobic regions.

As shown in the picture to the right, the two α-subunits are colored orange in this homeric receptor example. The two α-subunits each contain a ligand binding site colored red. Cys-192 and Cys-193, which are close proximity to the allosteric binding sites on the α-subunits for acetylcholine have been experimentally tested to show that disulfide residues provides stability in the binding of the neurotransmitter. The image (bottom left) shows a simplified depiction of the main components of one of the binding sites in a nAChR. Acetylcholine is shown to interact with various amino acid residues but specifically with the series of amino acids: Tyrosine (Y), Cysteine (C), Cysteine (C), and Tyrosine (Y). The cysteine sulfide residues form the disulfide interaction which aids in acetylcholine binding. The disulfide bonds facilitate the loop formations necessary for the appropriate bonds being formed with acetylcholine.

Medical Applications

References