Molecular Structure and Mechanism of Action
Unlike receptors that transmit signals through a cascade of secondary messengers, 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 end-plate of the neuromuscular junction as an example. The receptor consists of five protein subunits that form a ring around a sodium channel:
- Two $\alpha$-subunits;
- One $\beta$-subunit;
- One $\gamma$-subunit;
- One $\delta$-subunit.
The activation mechanism takes a fraction of a second and includes the following steps:
- Two molecules of the endogenous neurotransmitter (acetylcholine) bind to specific sites on both $\alpha$-subunits.
- In response, the central $Na^+$ channel opens.
- $Na^+$ ions rush into the cell in a cascade.
- Depolarization of the postsynaptic membrane occurs.
- A physiological response—muscle contraction—is triggered.
Classification and Localization
Receptor classification is based on their localization and the effects of their stimulation. There are two fundamental subtypes: muscle-type and neuronal-type.
$N_m$-Cholinoceptors (Muscle-Type)
These 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.
$N_n$-Cholinoceptors (Neuronal-Type)
This subtype has a significantly broader localization and mediates 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. Upon activation, they trigger the secretion of catecholamines—epinephrine and norepinephrine.
- Carotid bodies. These structures are located in the carotid sinus region 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 a shared sensitivity to nicotine and an ionotropic working principle, nicotinic receptors are not completely 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 various subtypes of $\alpha$- and $\beta$-subunits. These structural nuances account for the vast diversity of effects in the CNS and ganglia compared to the uniform response seen in muscles.
Pharmacological proof of this heterogeneity is demonstrated by drug selectivity. Substances that stimulate autonomic ganglia (ganglionic stimulants) affect skeletal muscle receptors only at significantly higher doses.