title: Intrinsically low open probability of α7 nicotinic acetylcholine receptors can be overcome by positive allosteric modulation and serum factors leading to the generation of excitotoxic currents at physiological temperatures.
abstract: α7 nicotinic acetylcholine receptors (nAChRs) have been a puzzle since their discovery in brain and non-neuronal tissues. Maximal transient probability of an α7 nAChR being open with rapid agonist applications is only 0.002. The concentration dependence of α7 responses measured from transfected cells and Xenopus laevis oocytes shows the same disparity in potency estimations for peak currents and net charge, despite being studied at 1000-fold different time scales. In both cases the EC₅₀ was approximately 10-fold lower for net charge than for peak currents. The equivalence of the data obtained at such disparate time scales indicates that desensitization of α7 is nearly instantaneous. At high levels of agonist occupancy, the receptor is preferentially converted to a ligand-bound nonconducting state, which can be destabilized by the positive allosteric modulator N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea (PNU-120596). Such currents can be sufficiently large to be cytotoxic to the α7-expressing cells. Both the potentiating effect of PNU-120596 and the associated cytotoxicity have a high temperature dependence that can be compensated for by serum factors. Therefore, despite reduced potentiation at body temperatures, use of type II positive allosteric modulators may put cells that naturally express high levels of α7 nAChRs, such as neurons in the hippocampus and hypothalamus, at risk. With a low intrinsic open probability and high propensity toward the induction of nonconducting ligand-bound states, it is likely that the well documented regulation of signal transduction pathways by α7 nAChRs in cells such as those that regulate inflammation may be independent of ion channel activation and associated with the nonconducting conformational states.
authors: Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, Florida, USA.
authors: Dustin K
authors: DK
authors: Williams
authors: Can
authors: C
authors: Peng
authors: Matthew R
authors: MR
authors: Kimbrell
authors: Roger L
authors: RL
authors: Papke
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D002417:Cattle; D003603:Cytotoxins / Q000494:pharmacology; D004357:Drug Synergism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D013696:Temperature; D014162:Transfection; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C579167:Chrna7 protein, human; D003603:Cytotoxins; D047908:Intracellular Signaling Peptides and Proteins; D007555:Isoxazoles; D010671:Phenylurea Compounds; C496701:RIC3 protein, human; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D012710:Serum Albumin, Bovine; D000109:Acetylcholine