By Flavio Guzman, MD. Pharmacology Department. University of Mendoza. Argentina
A number of drugs target acetylcholine receptors, blockade of these receptors is associated with anticholinergic (parasympatholytic) effect, while stimulation causes activation of cholinergic (parasympathomimetic) effects.
This articles overviews the key concepts on the pharmacology of acetylcholine receptors, such as:
Acetylcholine is released from a presynaptic neuron into the synaptic cleft. Once in the synaptic gap, acetylcholine can:
- Bind to presynaptic receptors: presynaptic activation or inhibition leads to automodulation of the presynaptic cholinergic neuron.
- Be degradated by acetylcholinesterase: activity of this enzime on acetylcholine triggers its degradation into choline and acetyl coenzime A, thus terminating its effect.
- Bind to postsynaptic receptors: activation of these receptors by acetylcholine leads to cholinergic response.
The figure below shows the two main families of acetylcholine receptors: muscarinic and nicotinic. In structural terms, muscarinic receptors are G-coupled protein receptors, while nicotinic receptors are ligand-gated ion channels. They can be found on both sides of the synaptic cleft (presynaptic and postsynaptic). However, for clinical purposes, we are focusing only on postsynaptic receptors.
Acetylcholine is a key neurotransmitter acting on a wide number of functions and tissues. This figure shows the three main locations of acetylcholine receptors:
CNS receptors (muscarinic and nicotinic): cholinergic neurotransmission at the CNS level is thought to regulate sleep, wakefulness, and memory. Two clinical situations depict the role of acetylcholine in CNS:
- Acetylcholinesterase inhibitors are used in the treament of Alzheimer’s disease and other dementias. Inhibition of the enzime that catalyzes acetylcholine degradation (acetylcholinesterase) produces an increased concentration of acetylcholine at the synaptic cleft, thus potentiating cholinergic neurotransmission. Examples of these drugs include donepezil and rivastigmine.
- Drugs that possess anticholinergic properties may cause acute encephalopathy, such as delirium or a confusional state. Some over-the-counter medications such as diphenidramine (an antihistamine) can cause cholinergic blockade that may lead to a decompensation of underlying cognitive, functional and behavioral deficits (particularly in patients with Alzheimer’s disease).
Autonomic receptors: they are present both in adrenergic and cholinergic transmission. They are discussed in the next section.
Neuromuscular junction: acetylcholine receptors at the neuromuscular junction are exclusively nicotinic, they belong to the NN subtype.
Acethylcholine acts on central and peripheral nervous systems ( the latter is divided into somatic and autonomic). The autonomic nervous system (ANS) exerts its actions through its two antagonic branches: sympathetic ( adrenergic) and parasympathetic (cholinergic).
Looking the diagram below we can see that both sympathetic and parasympathetic branches are modulated at the preganglionic level by the neurotransmitter acetylcholine. This molecule binds nicotinic receptors at the autonomic ganglia to trigger the release of norepinephrine (if a sympathetic synapse is stimulated) or acetylcholine that binds to tissue muscarinic receptors, which will produce a parasympathetic or cholinergic response.
Muscarinic receptors bind both acetylcholine and muscarine, an alkaloid present in certain poisonous mushrooms (it was first isolated in Amanita muscaria). Cholinergic transmission (acetylcholine-mediated) that activates muscarinic receptors occurs mainly at autonomic ganglia, organs innervated by the parasympathetic division of the autonomic nervous system and in the central nervous system.
All muscarinic receptors are G-protein coupled receptors. Binding studies have identified five subclasses of muscarinic receptors: M1,M2, M3, M4, and M5. The image below shows their locations:
M1, M4 and M5 receptors: CNS. These receptors are involved in complex CNS responses such as memory, arousal, attention and analgesia. M1 receptors are also found at gastric parietal cells and autonomic ganglia.
M2 receptors: heart. Activation of M2 receptors lowers conduction velocity at sinoatrial and atrioventricular nodes, thus lowering heart rate.
M3 receptors: smooth muscle. Activation of M3 receptors at the smooth muscle level produces responses on a variety of organs that include: bronchial tissue, bladder, exocrine glands, among others.
Unlike muscarinic receptors (which are G-protein coupled receptors), nicotinic receptors are ligand-gated ion channels. When bound to acetylcholine , these receptors undergo a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell.
Nicotinic receptors can be divided as the diagram shows:
N1 or NM receptors: these receptors are located at the neuromuscular junction, acetylcholine receptors of the NM subtype are the only acetylcholine receptors that can be found at the neuromuscular junction.
N2 or NN receptors: as mentioned before, nicotinic receptors play a key role in the transmission of cholinergic signals in the autonomic nervous systems. Nicotinic receptors of the NN subtipe can be found both at cholinergic and adrenergic ganglia, but not at the target tissues (e.g, heart, bladder, etc). These receptors are also present in the CNS and adrenal medulla.
You will also find useful the following article:
Beta adrenergic receptors: an article based on figures that highlight the key concepts of beta 1, 2, and 3 receptors.