Mini-Review Theme: NIDA Symposium: Drugs of Abuse: Cutting-edge Research Technologies

The AAPS Journal

, Volume 11, Issue 1, pp 167-177

Nicotine is a Selective Pharmacological Chaperone of Acetylcholine Receptor Number and Stoichiometry. Implications for Drug Discovery

  • Henry A. LesterAffiliated withDivision of Biology 156-29, California Institute of Technology Email author 
  • , Cheng XiaoAffiliated withDivision of Biology 156-29, California Institute of Technology
  • , Rahul SrinivasanAffiliated withDivision of Biology 156-29, California Institute of Technology
  • , Cagdas D. SonAffiliated withDivision of Biology 156-29, California Institute of Technology
  • , Julie MiwaAffiliated withDivision of Biology 156-29, California Institute of Technology
  • , Rigo PantojaAffiliated withDivision of Biology 156-29, California Institute of Technology
  • , Matthew R. BanghartAffiliated withDepartment of Neurobiology, Harvard Medical School
  • , Dennis A. DoughertyAffiliated withDivision of Chemistry and Chemical Engineering, California Institute of Technology
  • , Alison M. GoateAffiliated withWashington University School of Medicine
    • , Jen C. WangAffiliated withWashington University School of Medicine

Abstract

The acronym SePhaChARNS, for “selective pharmacological chaperoning of acetylcholine receptor number and stoichiometry,” is introduced. We hypothesize that SePhaChARNS underlies classical observations that chronic exposure to nicotine causes “upregulation” of nicotinic receptors (nAChRs). If the hypothesis is proven, (1) SePhaChARNS is the molecular mechanism of the first step in neuroadaptation to chronic nicotine; and (2) nicotine addiction is partially a disease of excessive chaperoning. The chaperone is a pharmacological one, nicotine; and the chaperoned molecules are α4β2* nAChRs. SePhaChARNS may also underlie two inadvertent therapeutic effects of tobacco use: (1) the inverse correlation between tobacco use and Parkinson’s disease; and (2) the suppression of seizures by nicotine in autosomal dominant nocturnal frontal lobe epilepsy. SePhaChARNS arises from the thermodynamics of pharmacological chaperoning: ligand binding, especially at subunit interfaces, stabilizes AChRs during assembly and maturation, and this stabilization is most pronounced for the highest-affinity subunit compositions, stoichiometries, and functional states of receptors. Several chemical and pharmacokinetic characteristics render exogenous nicotine a more potent pharmacological chaperone than endogenous acetylcholine. SePhaChARNS is modified by desensitized states of nAChRs, by acid trapping of nicotine in organelles, and by other aspects of proteostasis. SePhaChARNS is selective at the cellular, and possibly subcellular, levels because of variations in the detailed nAChR subunit composition, as well as in expression of auxiliary proteins such as lynx. One important implication of the SePhaChARNS hypothesis is that therapeutically relevant nicotinic receptor drugs could be discovered by studying events in intracellular compartments rather than exclusively at the surface membrane.

Key words

ADNFLE dopamine GABA proteostasis upregulation