8/18/2019 Acetylcholine receptors: muscarinic and nicotinic :: Reader View

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Acetylcholine receptors: muscarinic and nicotinic

6-8 minutes

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:

What happens after acetylcholine is released?

Classification of acetylcholine receptors

Location

Acetylcholine receptors and the autonomic nervous system

Muscarinic receptors

Nicotinic receptors

What happens after acetylcholine is released?

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.

Classification of acetylcholine receptors

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

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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.

Location of acetylcholine 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.

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Acetylcholine receptors  and the autonomic nervous system

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

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:

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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.

Nicotinic receptors

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:

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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.

References and further reading

Golan, David E (editor). “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd

edition. LWW: 2008.

Katzung, B. “Basic & Clinical Pharmacology”, 10th Edition. Mc Graw Hill Medical: 2007

Harvey, Richard; Champe, Pamela (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th

edition. LWW: 2009

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