title: Inside-out neuropharmacology of nicotinic drugs.
abstract: Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as "inside-out pharmacology". This term contrasts with the better-known, acute, "outside-in" effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.
authors: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors: Brandon J
authors: BJ
authors: Henderson
authors: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: Lester@Caltech.edu.
authors: Henry A
authors: HA
authors: Lester
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009480:Neuropharmacology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014029:Tobacco Use Disorder / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D009538:Nicotine
keywords: Chaperoning; Nicotine; Nicotine addiction; Nicotinic receptors; Unfolded protein response; Upregulation