Neurophysiology Modules

Module 6: Acetylcholine

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Introduction

There are two major subtypes of acetylcholine (cholinergic) receptors: nicotinic and muscarinic receptors. Both nicotinic and muscarinic receptors are present in the central nervous system. In addition, acetylcholine is used as a neurotransmitter by neurons that constitute the peripheral nervous system, including motoneurons, sympathetic and parasympathetic preganglionic neurons, and parasympathetic postganglionic neurons.

Acetylcholine also differs from most neurotransmitters, in that it is NOT reuptaken into the neuron that released it. Instead, acetylcholine is broken down by an enzyme, acetylcholinesterase, which is present in abundance at cholinergic synapses.

Nicotinic Receptors

All nicotinic receptors are ionotropic: binding of acetylcholine to the receptor results in the opening of an ion channel. Nicotinic receptors are comprised of 5 subunits, arranged symmetrically around a central pore. At least 12 building blocks and 17 subtypes of nicotinic receptors have been discovered. One of these subtypes is located at the neuromuscular junction and another is located in autonomic ganglia, where sympathetic or parasympathetic preganglionic neurons synapse with postganglionic neurons. The other subtypes are located in the central nervous system, and can be either presynaptic or postsynaptic. The pharmacology of the two subtypes of nicotinic receptors in the periphery (the autonomic ganglion subtype and the neuromuscular junction subtype) is much simpler than that of the multiplicity of subtypes in the central nervous system. However, one of the brain subtypes (alpha-4 beta-2 nicotinic receptor) is of note, as it is the main mediator of nicotine dependence.

The three nicotinic receptor subtypes highlighted above (ganglion-type, muscle-type, alpha-4 beta-2) are a cation channel that allows both Na+ and K+ to move through the membrane when acetylcholine binds. The entry of Na+ predominates, so an EPSP occurs in the postsynaptic neuron.

Nicotinic receptors are so named because they bind nicotine, which serves as an agonist. In reality, the potency of nicotine as an agonist is less at the neuromuscular junction than in autonomic ganglia and many nicotinic receptors in the brain.

What you need to know: There are some fairly specific nicotinic receptor agonists and antagonists (receptor blockers) with selective effects on synaptic transmission to muscle or in the autonomic nervous system. Here are some examples:

Nicotinic Receptor	Selective Agonist	Selective Antagonist
Muscle Type	Suxamethonium chloride (succinylcholine)	Pancuronium bromide
Ganglion Type	Dimethylphenylpiperazinium	Trimetaphan

Muscarinic Receptors

Unlike nicotinic receptors, muscarinic receptors are metabotropic: they are linked with G proteins. As such, binding of acetylcholine to a muscarinic receptor can elicit a host of effects in the postsynaptic neuron. Muscarinic receptors are so named because they bind muscarine, a product of some mushrooms.

Muscarinic receptors are located on the peripheral targets of the parasympathetic nervous system (like smooth muscle cells and secretory cells), a limited number of targets of the sympathetic nervous system (e.g., sweat glands), and in the central nervous system.

There are 5 major subtypes of muscarinic receptors: M1-M5. All of these subtypes are found in the central nervous system, and the M1-M3 subtypes are found in the periphery (on the targets of parasympathetic and a few sympathetic postganglionic neurons).

Many peripheral tissues have more than one muscarinic receptor subtype, such that it is difficult to predict the effects of applying acetylcholine (or a muscarinic receptor antagonist) to a particular tissue. It is thus also difficult to provide an agonist or antagonist for a muscarinic receptor that does not produce effects in many tissues.

That being said, one can draw some generalities about the different subtypes of muscarinic receptors, which are summarized in the table below:

Subtype	Effects and Localization
M1	Agonist causes a slow EPSP and a decrease in K+ conductance Located in salivary glands, GI tract
M2	Agonist causes an increased K+ conductance and a decrease in Ca2+ conductance Located in the heart (slows heart rate and conduction of electrical potentials)
M3	Many effects through G protein. Located in salivary glands, eye (accommodation), GI tract, Internal urinary sphincter

What you need to know: Most muscarinic agonists and antagonists have effects on multiple receptor subtypes. In addition, most tissues contain more than one muscarinic receptor subtype. Thus, altering a specific physiological function with a drug that acts on muscarinic receptors is difficult.

For example, the muscarinic receptor antagonist atropine induces dry mouth, large pupils, urinary retention, constipation, and a fast heart rate (it acts at many sites to produce many effects).

Messing with Cholinergic Neurotransmission

A variety of pharmacological approaches can be used to alter cholinergic neurotransmission, in addition to the delivery of cholinergic agonists and antagonists. These approaches include:

1. Use of acetylcholinesterase inhibitors. Such drugs delay the breakdown of acetylcholine, so the effects of the neurotransmitter persist over a longer time. Examples include neostigmine (used to treat myasthenia gravis, an autoimmune disease that results in loss of functional nicotinic receptors at the neuromuscular junction).
2. Use of Botulinum toxins. Such drugs interfere with the activity of proteins that are critical for the binding of vesicles containing acetylcholine to the membrane at the nerve terminal. Thus, the toxins prevent release of acetylcholine from the presynaptic terminal. They are injected into particular facial muscles as a cosmetic treatment (paralyzing facial muscles can eliminate wrinkles), or are used to relax spastic muscles.