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GEN News Highlights : Dec 31, 2013
Break Smoking’s Grip by Thwarting Nicotine’s Intracellular Machinations?
Nicotine promotes addiction by exploiting transport mechanisms within individual cells. Details of nicotine’s actions within cells, if brought to light, could suggest new strategies for smoking cessation. In addition, cellular mechanisms influenced by nicotine appear to have a role in reducing susceptibility to Parkinson’s disease, and so a better understanding of these mechanisms might also point to ways to prevent or slow Parkinson’s.
With such potential benefits in mind, researchers from the California Institute of Technology took a close look at the way nicotine activates nicotinic acetylcholine receptors (nAChRs) in the brains of mice. The researchers found that nicotine, unlike most other drugs of abuse, acts as a “pharmacological chaperone” to stabilize assembly of nAChRs within the endoplasmic reticulum (ER) and increase their abundance at the cell surface, thereby up-regulating them. It is by up-regulating nAChRs that nicotine fosters addiction and possibly contributes to protection against Parkinson’s disease.
The key finding, reported the researchers, is that the up-regulation depends on a coat protein complex I (COPI)-mediated process. COPI is a protein complex that coats vesicles for retrograde transport of proteins from the cis end of the Golgi to the endoplasmic reticulum.
The researchers described their work in an article published December 30 in The Journal of General Physiology, in an article entitled, “Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors.” In this article, the authors showed that nicotine-induced up-regulation fails to occur with inhibition of COPI-mediated retrograde traffic from the Golgi to the ER, either through the mutation of a putative COPI-binding motif or through the use of the COPI inhibitor.
Receptors containing an α6 subunit (α6* nAChRs) are abundant in several specific brain regions. By using mice expressing α6 labeled with a fluorescent protein, the researchers showed that exposure to nicotine—at a level comparable to that in human smokers—up-regulated α6* nAChRs in these areas of the brain. Unexpectedly, the researchers discovered that nicotine's ability to up-regulate α6* nAChRs relied on the retrograde transport of α6* nAChRs back from the Golgi to the ER by COPI-coated vesicles. The authors believe that Golgi–ER cycling (involving COPI vesicles) may be a common mechanism for up-regulation of other nAChRs by nicotine.
In evaluating these results, the researchers considered how Golgi–ER cycling could serve as a new mechanistic target for drug discovery: “Discovery of the role played by Golgi–ER cycling in both α6β2β3 and α4β2 nAChRs may eventually provide additional avenues for nicotine addiction therapies. A hypothetical small molecule designed to bind to the [β3] KKK [motif] and disrupt COPI binding would prevent the Golgi–ER cycling in a manner similar to observations in this work. This inhibition of Golgi–ER cycling would prevent the up-regulation of β3-containing nAChRs and may produce effects similar to many antagonists that have shown clinical promise.”
“In the search for potential therapeutics,” the authors added, “the selective expression pattern of α6β2β3 nAChRs to just a few neuronal populations would render the targeting of β3 more selective than a drug that inhibits Golgi–ER cycling in general.”
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