Nicotinic Acetylcholine Receptors (NAChR)

  • The cholinergic system modulates many complex processes in the central and peripheral nervous system.1 Components of this system are important drug targets.
  • The cholinergic system has been implicated in numerous processes, including learning and memory,2 attentional processes, executive function, arousal, reward, mood, and pain.3
  • Dysregulation of this system has widespread health consequences, such as depression, anxiety, addiction (nicotine, alcohol), dementias, schizophrenia, Parkinson’s, Alzheimer’s, ADHD, and epilepsies.4 (Attachment A)
  • Nicotinic acetylcholine receptors (nAChRs) and Lynx proteins are key components of the cholinergic system, which are expressed in the CNS and peripheral nervous systems.
  • nAChRs are a family of ion channels that open after binding acetylcholine, allowing diffusion of Na+ & K+.5
  • Lynx proteins are a family of membrane-tethered extracellular proteins that bind to nAChRs and modulate the channel’s activity.

NAChRs and Nicotine

Nicotine’s powerful & addictive effects are caused by its modulation of nAChR activity.

  • Nicotine addiction begins when nicotine acts on neuronal nicotinic receptors, such as the nAChRs.
  • Nicotine activates the nAChRs expressed in the reward circuitry and other areas of the brain. causing the release of neurotransmitters such as dopamine, glutamate and GABA (γ-aminobutyric acid).6
  • Numerous studies have shown that nicotine improves cognitive functions such as attention and memory.7
  • There is a link between neurological & psychiatric disorders and smoking.6 Some scientists believe dysregulation of nAChRs is a key factor in the high levels of smoking seen in patients with schizophrenia (90% smoke), Parkinson’s, depression (50% smoke), ADHD.8

Therapeutic Modulation of the Cholinergic System

  • There are many marketed and development-stage drugs that modulate the cholinergic system. Given this system’s important physiological roles, the function of these drugs spans a wide range of disorders. Examples include:

Gradient of Cholinergic Activation9

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Nicotinic Receptor Structure

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These nAChRs are made up of five proteins, or subunits, each of which traverses the cell membrane. There are two subunit types called alpha an beta. Together, the five subunits form a complex around a central pore or channel, similar to staves around a barrel.1011 When the nAChR binds acetylcholine, the channel opens and allows diffusion of sodium (Na+) and potassium (K+) ions.

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