Chapter 11

### INTRODUCTION

The nicotinic acetylcholine (ACh) receptor mediates neurotransmission postsynaptically at the neuromuscular junction and peripheral autonomic ganglia; in the CNS, it largely controls release of neurotransmitters from presynaptic sites. The receptor is called the nicotinic acetylcholine receptor because both the alkaloid nicotine and the neurotransmitter ACh can stimulate the receptor. Distinct subtypes of nicotinic receptors exist at the neuromuscular junction and the ganglia, and several pharmacological agents discriminate between the receptor subtypes.

### THE NICOTINIC ACETYLCHOLINE RECEPTOR

The binding of ACh to the nicotinic ACh receptor initiates the end-plate potential (EPP) in muscle or an excitatory postsynaptic potential (EPSP) in peripheral ganglia, as was introduced in Chapter 8. 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 of natural toxins that block motor activity, peripheral and then central nicotinic receptors were isolated and characterized. These accomplishments represent landmarks in the development of molecular pharmacology.

History. The electrical organs from the aquatic species of Electrophorus and Torpedo provide rich sources of nicotinic receptor. The electrical organ is derived embryologically from myoid tissue; however, in contrast to vertebrate skeletal muscle, in which motor end plates occupy 0.1% or less of the cell surface, up to 40% of the surface of the electric organ's membrane is excitable and contains cholinergic receptors. The discovery of seemingly irreversible antagonism of neuromuscular transmission by α-toxins from venoms of the krait, Bungarus multicinctus, or varieties of the cobra, Naja naja, offered suitable markers for identification of the receptor. The α-toxins are peptides of ~7 kDa. Radioisotope-labeled toxins were used in 1970 to assay the isolated cholinergic receptor in vitro (Changeux and Edelstein, 1998). The α-toxins have extremely high affinities and slow rates of dissociation from the receptor, yet the interaction is non-covalent. In situ and in vitro, their behavior resembles that expected for a high-affinity antagonist. Since cholinergic neurotransmission mediates motor activity in marine vertebrates and mammals, a large number of peptide, terpinoid, 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).

Purification of the receptor from Torpedo ultimately led to isolation of complementary DNAs for each of the subunits. These cDNAs, in turn, permitted the cloning of genes encoding the multiple receptor subunits from mammalian neurons and muscle (Numa et al., 1983). By simultaneously expressing various permutations of the genes that encode the individual subunits in cellular systems and then measuring binding and the electrophysiological events that result from activation by agonists, researchers have been able to correlate functional properties with details of primary structures of the receptor subtypes (Changeux and Edelstein, 2005; Karlin, 2002; Sine et al., ...

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