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Subcellular basis of nicotine-induced receptor upregulation

Institution: California Institute of Technology
Investigator(s): Rahul Srinivasan, Ph.D.
Award Cycle: 2009 (Cycle 18) Grant #: 18FT-0066 Award: $135,000
Subject Area: Nicotine Dependence
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Cigarette smoking causes the death of nearly half a million Americans each year. Nicotine, the primary active component of tobacco exerts its addictive effects by binding to proteins called the neuronal nicotinic acetylcholine receptors (nAChRs). nAChRs possess a central pore for the passage of calcium and sodium ions into the cell from the external environment. Proteins called subunits are arranged around this central pore to form a receptor. nAChRs are activated upon binding to nicotine and allow calcium ions to enter the cell. In a chronic smoker, the persistent activation of nAChRs results in an increased number of receptor subunits that assemble in nerve cells of the brain to form functional receptors. This phenomenon, called upregulation has been identified as (i) the primary reason for nicotine addiction and (ii) the cause for relapses that can occur after quitting smoking. To study the mechanisms of upregulation by nicotine, I have created nAChR subunits tagged with fluorescent proteins so that they can be directly visualized in live cells using fluorescence illumination and microscopy. I will use specialized high-resolution microscopy methods to study changes in nAChR subunit assembly and movement of fluorescently tagged nAChRs within sub-regions of nicotine treated cells and at the surface of the cell. In addition, I will try to identify cellular unique processes and molecules that can control the assembly and movement of nAChRs in cells with and without exposure to nicotine. Success in these experiments will allow the identification of key processes that cause nAChR upregulation following exposure to nicotine. This can potentially lead to the development of a new generation of drugs that can specifically reduce the number of nAChRs in a smoker’s brain without side-effects thus minimizing the chances of relapse.

Nicotine up-regulates a4B2 nicotinic receptors and ER exit sites via stoichiometry-dependent_x000D_ chaperoning
Periodical: Journal of General Physiology Index Medicus:
Authors: Srinivasan R, Pantoja R, Moss FJ, et al. ART
Yr: 2011 Vol: 137 Nbr: 1 Abs: Pg: 59-79

Trafficking of a4* nicotinic receptors revealed by superecliptic phluorin: effects of a B4 amyotrophic lateral sclerosis-associated mutation and chronic exposure to nicotine
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Richards CI, Srinivasan R, Xiao C, Mackey ED, Miwa JM, Lester HA. ART
Yr: 2011 Vol: 286 Nbr: 36 Abs: Pg: 31241-31249

Characterizing functional a6B2 nicotinic acetylcholine receptors in vitro: mutant B2 subunits improve membrane expression, and fluorescent proteins reveal responsive cells.
Periodical: Biochemical Pharmacology Index Medicus:
Authors: Xiao C *, Srinivasan R *, Drenan RM, Mackey ED, McIntosh JM, Lester HA. ART
Yr: 2011 Vol: 82 Nbr: 8 Abs: Pg: 852-861

Pharmacological chaperoning of nicotinic acetylcholine receptors reduces the_x000D_ endoplasmic reticulum stress response
Periodical: Molecular Pharmacology Index Medicus:
Authors: Srinivasan R, Richards CI, Xiao C, et al. ART
Yr: 2012 Vol: 81 Nbr: 6 Abs: Pg: 759-769

Forster Resonance Energy Transfer (FRET) Correlates of Altered Subunit Stoichiometry in Cys-Loop Receptors, Exemplified by Nicotinic a4B2.
Periodical: International Journal of Molecular Sciences Index Medicus:
Authors: Srinivasan R, Richards CI, Dilworth C, Moss Fl, Dougherty DA, Lester HA ART
Yr: 2012 Vol: 13 Nbr: 8 Abs: Pg: 10022-10040

Psychiatric Drugs Bind to Classical Targets Within Early Exocytotic Pathways:_x000D_ Therapeutic Effects
Periodical: Biological Psychiatry Index Medicus:
Authors: Lester HA, Miwa JM, Srinivasan R. ART
Yr: Vol: Nbr: Abs: Pg: