Nicotinic Acetylcholine Receptor - Opening The Channel

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. It is permeable to Na+ and K+, with some subunit combinations that are also permeable to Ca2+. 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.

It is interesting to note that, because some neuronal nAChRs are permeable to Ca2+, they can affect the release of other neurotransmitters. The channel usually opens rapidly and tends to remain open until the agonist diffuses away, which usually takes about 1 millisecond. 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.

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 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.