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Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists.

ABSTRACT: Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between acetylcholine (ACh) and weak partial agonists. Data were best-fit to a basic competition model that included an additional factor for noncompetitive inhibition. Partial agonist effects were compared with the nAChR antagonist bupropion in prolonged bath application experiments that were designed to mimic prolonged drug exposure typical of therapeutic drug delivery. A primary effect of prolonged application of nicotine was to decrease the response of all nAChR subtypes to acute applications of ACh. In addition, nicotine, cytisine, and varenicline produced detectable steady-state activation of ?4?2* [(?4)(2)(?2)(3), (?4)(3)(?2)(2), and (?4)(2)(?2)(2)?5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of ?7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, "run-up" of ?7 ACh responses was also sometimes observed under control conditions. Potential off-target effects of the partial agonists therefore included the modulation of ?7 responses by ?4?2 partial agonists and decreases in ?4?2* responses by ?7-selective agonists. These data indicate the dual effects expected for ?4?2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development.

SUBMITTER: Papke RL

PROVIDER: S-EPMC3083103 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists.

Papke Roger L RL Trocmé-Thibierge Caryn C Guendisch Daniela D Al Rubaiy Shehd Abdullah Abbas SA Bloom Stephen A SA

The Journal of pharmacology and experimental therapeutics 20110201 2

Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between a ...[more]

PMID: 21285282

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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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Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists.

Publications

Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists.

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