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.

Smoking-Relevant Nicotine Concentration Attenuates the Unfolded Protein Response in Dopaminergic Neurons

“…We have not worked previously with CHOP antibodies. Many commercially available CHOP antibodies fail evaluations for specificity, as discovered by Haataja et al (2008). Haataja et al (2008) recommended verifying that a known inducer of ER stress, such as Tu, does increase the level of nuclear CHOP.…”

“…Many commercially available CHOP antibodies fail evaluations for specificity, as discovered by Haataja et al (2008). Haataja et al (2008) recommended verifying that a known inducer of ER stress, such as Tu, does increase the level of nuclear CHOP. We therefore performed pilot experiments with a CHOP antibody, Santa Cruz Biotechnology sc-575 (1:250 dilution), also validated by Haataja et al (2008).…”

“…Unmitigated and maintained UPR activates a proapoptotic effector, C/EBP homologous protein (CHOP). Several authors suggest that CHOP partially underlies DA cell death and the development of Parkinson's disease (PD;Zinszner et al, 1998;Marciniak et al, 2004;Silva et al, 2005;Galehdar et al, 2010;Mercado et al, 2013).…”

The Nicotine Metabolite, Cotinine, Alters the Assembly and Trafficking of a Subset of Nicotinic Acetylcholine Receptors

“…It is possible that cotinine-induced up-regulation results from a similar mechanism as nicotine, likely acting inside the cell by binding immature subunits to enhance the maturation and stabilization of nAChRs (18,52). This chaperoning process is not unique to nicotine, and can potentially occur with any ligand that readily permeates cell membranes and interacts with intracellular nAChRs.…”

Adverse effects of perinatal nicotine exposure on reproductive outcomes

“…Nicotine can easily traverse membrane barriers due to its lipophilic nature and activate nicotinic acetylcholine receptors (nAChRs) (Langley 1905, Henderson & Lester 2015. Endogenous agonists such as acetylcholine normally bind nAChRs to regulate downstream cellular and physiological responses; however, exogenous agents like nicotine can compete for the binding sites and exert alternative, and potentially pathological, effects (Albuquerque et al 2009).…”