Drug Actions on Nicotinic Receptors. Chronic vs Acute; Outside-in vs Inside-out

Abstract

The superfamily of nicotinic acetylcholine receptors (nAChRs) comprises various homopentameric and heteropentameric ligand-gated channels (such as alpha7 and alpha4beta2*, respectively). Continuing studies show how the acute effects of exposure to nicotine (ms to min) arise from an ''outside-in'' event: activation and desensitization of sodium, potassium, and calcium selective ion channels in the various nAChRs. The ''outside-in'' events of nicotine resemble the actions of acetylcholine itself. These events are becoming known on the neuroanatomical scale of micrometers, the time scale of ms, the structural distance scale ofA ° , and the genomic resolution of single bp. Methods: Evolving methods are also revealing new features of nicotinic drug action during **chronic** exposure (hr to wk). The new methods include fluorescently labeled nAChRs, expressed both in knock-in mice and in cultured model systems; proteomics of molecules that interact with nAChRs; and RNA-Seq of genes activated by chronic nicotine. Results: An ''inside-out'' mechanism is becoming a likely mechanism to explain some chronic actions of nicotine and other nicotinic drugs. The "inside-out" pathway occurs at much lower nicotine concentrations than channel activation. The ''inside-out'' pathway begins with pharmacological chaperoning: nicotine and related drugs permeate into the cytoplasm, then into the endoplasmic reticulum. There, the drugs interact with nAChRs and stabilize some nascent nAChRs. The best-known result of "inside-out" action is the classical posttranslational ''upregulation'' of some nAChRs. In addition, the ''inside-out'' pathway also leads, via pharmacological chaperoning, to other events including decreased endoplasmic reticulum stress, decreased unfolded protein response, and possibly perturbed nAChR interactions with other molecules. Conclusions: The ''inside-events'' are not straightforward continuations of transduction pathways activated during ''outside-in'' activation and desensitization, but result when prolonged (hr to wk) nicotine binding to intracellular nAChRs activates an entirely different set of pathways. The ''inside-out'' pathway is accreting many biophysical, biochemical, thermodynamic, cell biological, neuroanatomical, and electrophysiological details. Yet, ''inside-out'' mechanisms have arisen, in part, from re-examining classical pharmacokinetic and pharmacodynamic facts: nicotine can interact with intracellular molecules many orders of magnitude more strongly than can the endogenous neurotransmitter, acetylcholine. There is no current evidence that the ''inside-out'' events have counterparts in the normal cell or organismic biology of nAChRs. The present challenge is pursue the hypothesis that the ''insideout'' events have the power and selectivity to underlie two aspects of chronic exposure to nicotine: nicotine dependence and apparent neuroprotection. Disclosure: Nothing to Disclose.

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