Nicotinic Receptors

Molecular structure and mechanism of action

Unlike receptors that transmit signals via a second-messenger cascade, the nicotinic acetylcholine receptor is ionotropic. This means it is directly linked to an ion channel spanning the postsynaptic membrane.

Chemically, it is a complex glycoprotein. Let us examine its molecular structure using the endplate of the neuromuscular synapse as an example. The receptor consists of five protein subunits forming a ring around a sodium channel:

• Two $\alpha$-subunits;
• One $\beta$-subunit;
• One $\gamma$-subunit;
• One $\delta$-subunit.

The activation mechanism takes place within fractions of a second and includes the following steps:

1. Two molecules of the endogenous neurotransmitter (acetylcholine) bind to specific sites on both $\alpha$-subunits.
2. In response, the central $Na^+$ channel opens.
3. $Na^+$ ions rush into the cell in an avalanche-like manner.
4. Depolarization of the postsynaptic membrane occurs.
5. A physiological response is triggered — muscle contraction.

Classification and localization

Receptor classification is based on their localization and the effects of stimulation. There are two fundamental subtypes: muscle and neuronal.

$N_m$-cholinergic receptors (muscle type)

They are located exclusively on the postsynaptic membranes of skeletal muscle, forming neuromuscular junctions. Their sole function is to ensure skeletal muscle contraction in response to a nerve impulse.

$N_n$-cholinergic receptors (neuronal type)

This subtype has a significantly broader localization and is responsible for a spectrum of physiological responses. $N_n$-receptors are found in the central nervous system as well as in the following structures:

• Autonomic ganglia (both sympathetic and parasympathetic). The result of their stimulation is the excitation of ganglionic neurons.
• Adrenal medulla. The receptors are located on chromaffin cells. Their activation triggers the secretion of catecholamines — adrenaline and noradrenaline.
• Carotid bodies. These structures are located in the sinocarotid zone — at the bifurcation of the common carotid arteries. Excitation of local $N_n$-receptors causes reflex stimulation of the vasomotor and respiratory centers.

Receptor heterogeneity

Despite their general sensitivity to nicotine and ionotropic mechanism of action, nicotinic acetylcholine receptors are not identical across all tissues.

The main difference between the neuronal (ganglionic) and muscle types lies in their subunit composition. While the $N_m$-receptor includes four different types of subunits ($\alpha$, $\beta$, $\gamma$, $\delta$), the $N_n$-receptor consists exclusively of $\alpha$- and $\beta$-subunits of various subtypes. It is these structural nuances that determine the vast diversity of effects in the CNS and ganglia compared to the uniform response of muscles.

Pharmacological evidence of heterogeneity is the selectivity of drug action. Substances that stimulate autonomic ganglia (ganglioplegics/ganglion stimulants) can affect skeletal muscle receptors only at significantly higher doses.

Class and exam questions

What else to study on this topic

• The mechanism of catecholamine release by adrenal medullary cells
• The role of the sinocarotid zone in the reflex regulation of respiration
• Differences in the subunit composition of central nervous system nicotinic acetylcholine receptors
• The use of ganglion stimulants in pharmacological practice

Other topics in the section «Drugs acting on cholinergic synapses»

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