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Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors.

ABSTRACT: Nicotinic acetylcholine receptors are a diverse set of ion channels that are essential to everyday brain function. Contemporary research studies selective activation of individual subtypes of receptors, with the hope of increasing our understanding of behavioral responses and neurodegenerative diseases. Here, we aim to expand current binding models to help explain the specificity seen among three activators of ?4?2 receptors: sazetidine-A, cytisine, and NS9283. Through mutational analysis, we can interchange the activation profiles of the stoichiometry-selective compounds sazetidine-A and cytisine. In addition, mutations render NS9283--currently identified as a positive allosteric modulator--into an agonist. These results lead to two conclusions: (1) occupation at each primary face of an ? subunit is needed to activate the channel and (2) the complementary face of the adjacent subunit dictates the binding ability of the agonist.

SUBMITTER: Marotta CB

PROVIDER: S-EPMC4033646 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors.

Marotta Christopher B CB Rreza Iva I Lester Henry A HA Dougherty Dennis A DA

ACS chemical biology 20140305 5

Nicotinic acetylcholine receptors are a diverse set of ion channels that are essential to everyday brain function. Contemporary research studies selective activation of individual subtypes of receptors, with the hope of increasing our understanding of behavioral responses and neurodegenerative diseases. Here, we aim to expand current binding models to help explain the specificity seen among three activators of α4β2 receptors: sazetidine-A, cytisine, and NS9283. Through mutational analysis, we ca ...[more]

PMID: 24564429

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Project description:The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ?300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by ?Y190) that behaves similarly at all sites and a coupled pair (led by ?W55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of ?(1) and one each of ?, ?, and either ? (fetal) or ? (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at ?? and either ?? or ?? subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C?O opening rate constant and C?O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly to reach a peak that corresponds to PO ?0.96.

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Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors.

Publications

Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors.

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