Acetylcholine receptors are divided into two main types on the basis of their pharmacologic properties. Muscarine, the alkaloid responsible for the toxicity of toadstools, mimics the stimulatory action of acetylcholine on smooth muscle and glands. These actions of acetylcholine are called muscarinic actions, and the receptors involved are muscarinic cholinergic receptors. In sympathetic ganglia and skeletal muscle, nicotine mimics the stimulatory actions of acetylcholine. These actions of acetylcholine are called nicotinic actions, and the receptors involved are nicotinic cholinergic receptors. Nicotinic receptors are subdivided into those found in muscle at the neuromuscular junction (NM ) and those found in the CNS and autonomic ganglia (NN ). Both muscarinic and nicotinic acetylcholine receptors are also found within the brain.
The nicotinic acetylcholine receptors are members of a superfamily of ligand-gated ion channels (ionotropic receptors) that also includes the GABAA and glycine receptors and some of the glutamate receptors. Each nicotinic cholinergic receptor is made up of five subunits that form a central channel which, when the receptor is activated, permits the passage of Na+ and other cations. The five subunits come from several types designated as α, β, γ, δ, and ε that are each coded by different genes. The NM receptor is comprised of two α, one β, one δ, and either one γ or one ε subunit (Figure 1). The NN receptors are comprised of only α and β subunits. Each α sub unit has a binding site for acetylcholine, and binding of an acetylcholine molecule to each of them induces a conformational change in the protein so that the channel opens. This increases the conductance of Na+, and the resulting influx of Na+ pro duces a depolarizing potential. A prominent feature of neuronal nicotinic cholinergic receptors is their high permeability to Ca2+. Many of the nicotinic cholinergic receptors in the brain are located presynaptically on glutamate-secreting axon terminals, and they facilitate the release of this transmitter.
Fig1. Three-dimensional model of the nicotinic acetylcholine-gated ion channel. The receptor–channel complex consists of five subunits, all of which contribute to forming the pore. When two molecules of acetylcholine bind to portions of the α-subunits exposed to the membrane surface, the receptor—channel changes conformation. This opens the pore in the portion of the channel embedded in the lipid bilayer, and both K+ and Na+ flow through the open channel down their electrochemical gradient. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. New York, NY: McGraw-Hill; 2000.)
There are five types of muscarinic cholinergic receptors (M1–M5 ), which are encoded by five separate genes. These are metabotropic receptors that are coupled via G-proteins to adenylyl cyclase, K+ channels, and/or phospholipase C (Table 1). M1 , M4 , and M5 receptors are located in the CNS; M2 receptors are in the heart, M3 are on glands and smooth muscle. M1 receptors are also located on autonomic ganglia where they can modulate neurotransmission.
Table1. Pharmacology of a selection of receptors for some small-molecule neurotransmitters.
