NAChRs

M. Bom, Nachr Akad. Wiii. Gdtt. Math.-Phys. Ki Article No. 6, 1 (1951). 

W. Huckel, Nachr. Akad. Wiss. Gottingen Math. Phys. Rl, 36 (1946). 

Acetylcholine. Acetylcholiae (ACh) (1) is a crystalliae material that is very soluble ia water and alcohol. ACh, synthesized by the enzyme choline acetyltransferase (3), iateracts with two main classes of receptor ia mammals muscarinic (mAChR), defiaed oa the basis of the agonist activity of the alkaloid muscarine (4), and nicotinic (nAChR), based on the agonist activity of nicotine (5) (Table 1). m AChRs are GPCRs (21) n AChRs are LGICs (22). 

A systematic nomenclature for nAChRs has yet to evolve. An N nomenclature describes receptors present ia muscle as N. These are activated by phenyltrimethylammonium (PTMA) (15) and blocked by t5 -tubocurariae (16) and a-bungarotoxiu (a-BgT) (17). N2 receptors are present ia ganglia and are activated by l,l-dimethyl-4-phenylpipera2inium (DMPP) (18) and blocked by trimethaphan (19) and bis-quatemary agents, with hexamethonium (20) being the most potent. 

Like mAChRs, nAChRs have been implicated in the etiology of ALheimef s disease and related dementias as well as in gastrointestinal and cardiovascular disorders. Nicotine has high abuse potential and is the primary component in reinforcing smoking behaviors. Nicotine patches have been... 

Nicotinic receptors (nicotinic acetylcholine receptors, nACHR) exist not only in the membrane of vertebrate skeletal muscle at the synapse between nerve and muscle (muscle-type nAChR) but also at various synapses throughout the brain, mainly at presynaptic positions (neuronal-type nAChR). Whereas the muscle-type nAChR is precisely composed of two a 1-subunits, one (3 -subunit, one y -subunit and one y -subunit (adult)... 

The nicotinic receptor (nAChR) comprises a family of receptor subtypes that respond to the neurotransmitter acetylcholine (ACh) and the tobacco alkaloid nicotine. 

Skeletal muscle (muscle nAChR, comprised of al, 31,y or e, and 8 subunits, also present in electric tissues of Torpedo and Electrophorus)... 

Sympathetic, parasympathetic and sensory neurones, chromaffin, neuroblastoma and PC 12 cells (ganglionic nAChR, typically comprised of a3,a5,(32,(34 or al subunits)... 

CNS neurones (in mammals heteromeric nAChR comprised of a/(3 combinations from a2,a3,a4,-a5,a6,(32,(33,(34 subunits, or homomeric nAChR comprised of al subunits only)... 

The subtypes of nAChR that are not found in skeletal muscle are collectively referred to as neuronal nAChRs . 

The nAChR is comprised of five subunits, each of which spans the lipid bilayer to create a water-filled pore or channel (Fig. la). Each subunit consists of four transmembrane segments, the second transmembrane segment (M2) lines the ion channel (Fig. lb). The extracellular N-terminal domain of every subunit... 

Nature has created a diverse array of plant and animal toxins that act at mammalian muscle and ganglionic nAChRs or invertebrate nAChRs because the critical physiological functions of these receptors make them prime targets for defensive or predatory strategies. More recently, the perceived validity of neuronal nAChR as therapeutic targets has prompted the generation of new synthetic ligands. Examples are listed in Table 1. 

Agonists activate nAChR by binding to the agonistbinding site (Fig. 1). They can remain bound (often with higher affinity) when the nAChR enters the desensitised state. 

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