AUC: area under the curve
CNS: central nervous system
EPP: end-plate potential
EPSP: excitatory postsynaptic potential
FDA: Food and Drug Administration
GABA: γ-aminobutyric acid
5HT: 5-hydroxytryptamine (serotonin)
IPSP: inhibitory postsynaptic potential
MAO: monoamine oxidase
Mx: muscarinic receptor subtype x (x = 1, 2, 3, 4, or 5)
Nm: nicotinic ACh receptor in skeletal muscle
Nn: nicotinic ACh receptor in neurons
NRT: nicotine replacement therapy
SIF: small, intensely fluorescent
VMAT2: vesicular monoamine transporter 2
THE NICOTINIC ACETYLCHOLINE RECEPTOR
The nicotinic ACh receptor mediates neurotransmission postsynaptically at the neuromuscular junction and peripheral autonomic ganglia; in the CNS, it plays a major role in modulating the release of neurotransmitters from presynaptic sites. The receptor is called the nicotinic ACh receptor because both the alkaloid nicotine and the neurotransmitter ACh can stimulate the receptor. Distinct subtypes of nicotinic receptors, defined by their subunit composition, exist at the neuromuscular junction (Nm), in autonomic ganglia, and in the CNS (the neuronal form, Nn). The binding of ACh to the nicotinic ACh receptor initiates an EPP in muscle or an EPSP in peripheral ganglia by directly mediating cation influx into the postsynaptic cell (see Chapter 10).
Classical studies of the actions of curare and nicotine defined the concept of the nicotinic ACh receptor over a century ago and made this the prototypical pharmacological receptor. By taking advantage of specialized structures that have evolved to mediate cholinergic neurotransmission and natural toxins that block motor activity, nicotinic receptors were isolated and characterized (Changeux and Edelstein, 2005). These accomplishments represent historical landmarks in the development of molecular pharmacology.
Cholinergic neurotransmission mediates motor activity in marine vertebrates and mammals, and a large number of peptide, terpenoid, and alkaloid toxins that block the nicotinic receptors have evolved to enhance predation or protect plant and animal species from predation (Taylor et al., 2007; Tsetlin et al., 2021). Among these toxins are the α-toxins: peptides of about 7 kDa from venoms of the krait, Bungarus multicinctus, and varieties of the cobra, Naja naja. These toxins potently inhibit neuromuscular transmission, are readily radiolabeled, and provide excellent probes for the nicotinic receptor.
The electrical organs from the aquatic species of Electrophorus and Torpedo are rich sources of nicotinic receptors; up to 40% of the surface of the electric organ’s membrane is excitable and contains cholinergic receptors, in contrast to vertebrate skeletal muscle, in which motor end plates occupy 0.1% or less of the cell surface. Using the α-toxin probes, researchers have purified the receptor from Torpedo, isolated the cDNAs of the subunits, and cloned the genes for the multiple receptor subunits from mammalian neurons and muscle (Numa et al., 1983). By simultaneously ...