What are examples of nicotine acetylcholine receptors?

Nicotinic Acetylcholine Receptors: Types and Distribution

The most common nicotinic acetylcholine receptor subtype is α4β2, which has high affinity for nicotine and shows increased functional activity in the cortex, hippocampus, striatum, and thalamus during adolescence compared to adulthood. 1

Structure and Classification

Nicotinic acetylcholine receptors (nAChRs) are integral membrane proteins belonging to the ligand-gated ion channel superfamily. They have a pentameric structure composed of five transmembrane subunits arranged around a central cation core.

• nAChRs are formed by the assembly of five subunits selected from a pool of 17 homologous polypeptides (α1-10, β1-4, γ, δ, and ε) 2
• The mature nAChR has its glycoprotein subunits arranged around a central cation core, with two molecules of acetylcholine binding simultaneously to the two alpha subunits to convert the channel to an open state 1
• There are two main categories of nAChRs: muscle-type and neuronal-type receptors 2, 3

Muscle Nicotinic Acetylcholine Receptors

Muscle nAChRs are found at the neuromuscular junction where they mediate synaptic transmission.

• The mature muscle nAChR consists of α1, β1, δ, and ε subunits in a 2:1:1:1 ratio 1
• In fetal or denervated muscle, an immature or fetal-variant receptor is expressed where the γ subunit replaces the ε subunit 1
• These immature receptors have distinctive characteristics:
  • 10-fold greater ionic activity
  • Rapid metabolic turnover (<24 hours)
  • Extrajunctional proliferation across the entire membrane surface 1
  • More sensitive to depolarizing effects of drugs like succinylcholine 1

Neuronal Nicotinic Acetylcholine Receptors

Neuronal nAChRs are widely distributed throughout the central and peripheral nervous systems.

• The most common neuronal nAChR subtype is α4β2, which has high affinity for nicotine 1
• α4β2 receptors show higher functional activity in the cortex, hippocampus, striatum, and thalamus during adolescence (ages 13-18) than in adulthood 1
• Other important neuronal subtypes include:
  • α7 (homomeric receptors)
  • α3β4 (found predominantly in autonomic ganglia)
  • α6-containing receptors (important in dopaminergic pathways) 4, 5

Distribution in the Brain

nAChRs are distributed throughout various regions of the brain with specific subtype localization patterns.

• α4β2 receptors are widely distributed in the cerebral cortex, hippocampus, striatum, and thalamus 1, 6
• CB1 receptors (which can interact with nicotinic systems) are present in the cerebral cortex, hippocampus, basal ganglia, cerebellum, and peripheral nervous system 1
• Neuronal nAChRs mediate diverse physiological functions including cognition, reward, motor activity, and analgesia 4

Extraneuronal Nicotinic Acetylcholine Receptors

Recent research has identified nAChRs in numerous non-neuronal cell types.

• nAChRs are found in keratinocytes, epithelia, macrophages, endothelial cells, and immune cells 5
• In non-neuronal cells, these receptors regulate cell differentiation, proliferation, and inflammatory responses 5
• E-cigarettes deliver nicotine that acts on these receptors via an aerosol created by heating e-liquid nicotine concentrate 1

Clinical Significance

nAChRs are implicated in various pathological conditions and are important therapeutic targets.

• nAChRs are involved in myasthenia gravis, Alzheimer's disease, Parkinson's disease, schizophrenia, and nicotine addiction 2, 6
• Changes in sensitivity to neuromuscular blocking agents (NMBAs) can occur due to:
  • Up-regulation: increase in number or sensitivity of receptors, decreasing sensitivity to NMBAs 1
  • Down-regulation: decrease in number or sensitivity of receptors, increasing sensitivity to NMBAs (as in myasthenia gravis) 1
• Prolonged use of NMBAs in ICU settings can trigger changes in nAChRs, potentially leading to complications 1

Pharmacological Considerations

Understanding nAChR subtypes is crucial for drug development and clinical applications.

• Nicotine has high affinity for α4β2 receptors, which desensitize at nicotine concentrations lower than required for activation 1
• Flavored e-liquids often have lower pH than tobacco flavors, resulting in more rapid absorption of nicotine 1
• The lack of subtype-specific ligands has historically hampered identification of different native nAChR subtypes 4
• Development of subtype-specific drugs is an important area of research for treating various neurological and psychiatric disorders 2, 4