Structure, diversity, and ionic permeability of neuronal and muscle acetylcholine receptors

Nicotinic acetylcholine receptors (nAChRs) form a family of ligand-gated, cation-selective channels that are concentrated at cholinergic synapses on vertebrate neurons and muscle cells. At the neuromuscular endplate, muscle nAChRs bind acetylcholine released by the presynaptic motor neuron. The receptors then undergo a conformational change that opens their ion channels. Cations move passively through the water-filled pores down their electrochemical gradients, completing synaptic transmission by depolarizing the postsynaptic muscle. The channel only weakly discriminates among permeant cations, which include all monovalent and divalent cations that are small enough to fit through the narrowest cross section. The membrane-spanning region of the pore is lined by uncharged domains that are bracketed by residues with net negative charge. The pore has large entrance vestibules, especially facing extracellularly. The narrowest cross-section is located near the cytoplasmic end of the membrane-spanning region, and this short narrow region probably provides the main cation binding site that is directly in the permeation pathway. Neuronal nAChRs share many of the properties of muscle nAChRs, but the neuronal receptor subtypes are more heterogenous genetically, pharmacologically, and functionally. There are especially important functional differences between muscle and neuronal nAChRs. For example, neuronal nAChRs are more highly permeable to Ca2+ and physiological levels of Ca2+ very potently modulate neuronal nicotinic currents. This variety of nAChRs suggests that these receptor/channels serve many roles in the excitable tissues of vertebrates.