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

Download
index.pdf
2009-03-01
Lester, Henry A.
Xiao, Cheng
Srinivasan, Rahul
Son, Çağdaş Devrim
Miwa, Julie
Pantoja, Rigo
Banghart, Matthew R.
Dougherty, Dennis A.
Goate, Alison M.
Wang, Jen C.
Show full item record
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
127
views
0
downloads
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 alpha 4 beta 2* 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.
ADNFLE, Dopamine, GABA, Proteostasis, Upregulation
https://hdl.handle.net/11511/35293
Department of Biology, Article

Suggestions

Enantioselective Michael Addition of Nitroalkanes to Nitroalkenes Catalyzed by Chiral Bifunctional Quinine-Based Squaramides
KANBEROĞLU, Esra; Tanyeli, Cihangir (2016-01-01)
A family of chiral bifunctional acid-/base-type quinine/squaramide organocatalysts is shown to be highly active promoters of the conjugate addition of 1-nitropropane to various trans--nitroalkenes. The cooperation of the quinine and the sterically encumbered squaramide moieties catalyzed the Michael addition reactions at 0 degrees C by using a catalyst loading of only 2mol% to afford the 1,3-dinitro Michael adducts with excellent enantioselectivity and diastereoselectivity (up to 95%ee and syn/anti isomers ...
Isoquinolinedione-urea hybrids: Synthesis, antibacterial evaluation, drug-likeness, molecular docking and DFT studies
HAN, MUHAMMED İHSAN; Dengiz, Çağatay; Dogan, Sengul Diem; GÜNDÜZ, MİYASE GÖZDE; KÖPRÜ, SEMİHA; ÖZKUL KOÇAK, CEREN (2022-03-01)
In the present study, we applied the molecular hybridization approach to combine isoquinolinedione and urea pharmacophores in the same molecules. The hybrid compounds (IU1-IU14) were obtained by the reaction of 2-aminohomophthalimide and an equivalent amount of various isocyanate derivatives. After confirming the chemical structures and evaluating drug-likeness properties, the synthesized compounds were examined for their antibacterial activities against a wide range of bacteria. The compounds possessing li...
Specific Functions of Melanocortin 3 Receptor (MC3R)
Yanık, Tülin; Durhan, Seyda Tugce (2023-02-27)
Melanocortin 3 receptor (MC3R) is a G-protein coupled receptor which has been defined mostly as a regulator of the appetite/hunger balance mechanisms to date. In addition to its function regarding the weight gain and appetite control mechanisms of MC3R, recent studies have shown that MC3R controls growth, puberty, and circadian rhythms as well. Despite the drastic effects of MC3R deficiency in humans and other mammals, its cellular mechanisms are still under investigation. In this review paper, we aimed to ...
Systemic Delivery of Bioactive Glucagon-Like Peptide 1 after Adenoviral-Mediated Gene Transfer in the Murine Salivary Gland
Voutetakis, Antonis; Cotrim, Ana P.; Rowzee, Anne; Zheng, Changyu; Rathod, Trushar; Yanık, Tülin; Loh, Y. Peng; Baum, Bruce J.; Cawley, Niamh X. (2010-09-01)
Anadenoviral (Ad) vector that expresses bioactive glucagon-like peptide 1 (GLP-1) was generated, and its effectiveness at modulating glucose homeostasis was evaluated after transduction of murine salivary glands. The construct was engineered with the signal sequence of mouse GH to direct the peptide into the secretory pathway, followed by a furin cleavage site and the GLP-1(7-37) sequence encoding an Ala to Gly substitution at position 8 to achieve resistance to degradation. When expressed in Neuro2A and CO...
Squaramide catalyzed alpha-chiral amine synthesis
Karahan, SEDA; Tanyeli, Cihangir (2018-10-17)
Enantiomerically pure alpha-chiral amines, have been commonly utilized as resolving agents and chiral auxiliaries and are currently found in 40% of active pharmaceutical ingredients. Hence, development of highly stereoselective metal-free protocols regarding atom-economy and large-scale applications becomes a major issue. In this respect, chiral bifunctional H-bonding squaramides have been successfully applied for both amine synthesis and functionalization of amines in the last decade. This survey summarize...
Citation Formats
H. A. Lester et al., “Nicotine is a Selective Pharmacological Chaperone of Acetylcholine Receptor Number and Stoichiometry. Implications for Drug Discovery,” AAPS JOURNAL, pp. 167–177, 2009, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/35293.
METU IIS - Integrated Information Service open@metu.edu.tr