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INTRODUCTION

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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.

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THE NICOTINIC ACETYLCHOLINE RECEPTOR

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The binding of ACh to the nicotinic ACh receptor initiates an endplate potential (EPP) in muscle or an excitatory postsynaptic potential (EPSP) in peripheral ganglia (see Chapter 8). The nicotinic receptor is the prototype for other pentameric ligand-gated ion channels, which include the receptors for the inhibitory amino acids (γ-aminobutyric acid [GABA] and glycine; see Chapter 14) and serotonin (the 5HT3 receptor) (Figure 11-1).

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figure 11–1

Subunit organization of pentameric ligand-gated ion channels and the ACh binding protein. For each receptor, the amino terminal region of ~210 amino acids is found at the extracellular surface. It is then followed by 4 hydrophobic regions that span the membrane (TM1-TM4), leaving the small carboxyl terminus on the extracellular surface. The TM2 region is α-helical, and TM2 regions from each subunit of the pentameric receptor line the internal pore of the receptor. Two disulfide loops at positions 128-142 and 192-193 are found in the α-subunit of the nicotinic receptor. The 128-142 motif is conserved in the family of pentameric receptors; the vicinal cysteines at 192-193 occur only in α-subunits of the nicotinic receptor and in the ACh binding protein.

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NICOTINIC RECEPTOR STRUCTURE. Nicotinic receptors of vertebrate skeletal muscle (Nm) are pentamers composed of 4 distinct subunits (α, β, γ, and δ) in the stoichiometric ratio of 2:1:1:1. In mature, innervated muscle endplates, the γ subunit is replaced by ε, a closely related subunit. The individual subunits are ~40% identical in their amino acid sequences. The 5 subunits of the nicotinic acetylcholine receptor are arranged around a pseudo-axis of symmetry to circumscribe a channel. Agonist-binding sites occur at the subunit interfaces; in muscle, only 2 of the 5 subunit interfaces, αγ and αδ, bind ligands (Figure 11-2). Both of the subunits forming the subunit interface contribute to ligand specificity.

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figure 11–2

Subunit arrangement and molecular structure of the nicotinic acetylcholine receptor. A. Longitudinal view of receptor schematic with the γ subunit removed. The remaining subunits, 2 copies of α, 1 of β, and 1 of δ, are shown to surround an internal channel with an outer vestibule and its constriction located deep in the membrane bilayer region. Spans of α-helices with slightly bowed structures form the perimeter of the channel and come from the TM2 region of the linear sequence (Figure 11-1). ACh binding sites, indicated by red arrows, occur ...

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