Nicotinic Receptors and Disease: Barrow Study IDs Potential Drug Targets

Barrow scientists who study specific receptors in the brain say the findings from their latest study could have important ramifications for a wide array of cholinergic functions, such as enhancing cognition in people with dementia, repairing the brain after stroke, and smoking cessation.

Dr. Andrew George, a research assistant professor of neurobiology at Barrow, and his team used single-channel electrophysiological methods to demonstrate for the first time that an endogenous Ly-6 prototoxin known as lynx1 functionally interacts with a specific nicotinic acetylcholine receptor (nAChR) subtype known as the α3β4 nAChR subtype.

The study, published in the Federation of American Societies for Experimental Biology (FASEB) journal, provides valuable leads for drug design by offering new insights into the range of mechanisms and possible receptor sites by which such interactions can alter the function of these receptors.

“The resulting compounds, based on the endogenous lynx1 molecule, could be aimed at disrupting or encouraging these lynx1-α3β4 nAChR interactions, thereby shifting the physiological balances maintained by these interactions,” Dr. George explained. “Studies such as this can provide specific insight as to which novel endogenous Ly-6 genes can be targeted and then used during drug development.”

The Role of Acetylcholine Receptors

Andrew George, PhD
Research Assistant Professor

Nerve cells in the brain, or neurons, communicate through chemical messengers called neurotransmitters. When a neuron releases a neurotransmitter, it binds to another neuron via a receptor. Each receptor has a distinctly shaped region that recognizes a particular chemical messenger, such as acetylcholine. When the neurotransmitter is in place on the target neuron, a response such as a muscle contraction is triggered.

Acetylcholine is involved in a number of functions, including memory and motor functions. The neurons that send and receive acetylcholine make up the cholinergic system — an important pathway in the central nervous system. Cholinergic signaling has been associated with mood disorders, learning and memory problems, drug addiction, Parkinson’s disease, and Alzheimer’s disease.

There are different subtypes of nicotinic acetylcholine receptors. The α3β4 nAChR subtype, which was the focus of this study, is enriched in the habenulo-interpeduncular (MHb-IPN) pathway. This pathway, when activated, has been shown to mediate aversion to toxic substances such as nicotine.

Understanding Lynx1

The lynx molecules are part of the Ly-6 superfamily of genes, which Dr. George said are implicated in brain development and many brain functions as entities that can tweak but not abrogate or over-stimulate key chemical signaling pathways.

Dr. George also said it has long been known that Ly-6 genes, which are widely expressed in the central nervous system, are important in immune cell differentiation and signaling pathways within immune cells.

Studies such as this can provide specific insight as to which novel endogenous Ly-6 genes can be targeted and then used during drug development.

-Dr. Andrew George, Research Assistant Professor

“But within the past 10 years or so, we’ve identified that these genes can interact with nicotinic receptors themselves,” he said. “Lynx1 seems to modulate the α3β4 subtype in terms of tamping down its function, but what it can do in terms of the overall neuronal output is unknown at this point.”

That is one of the next steps for Dr. George and his team, along with trying to understand how information gained from this study can be used to identify different pharmaceutical compounds that can mimic the interaction and affect cellular output in a beneficial way.

“An exciting area of pharmacological design would be to synthetically create compounds based on the structure and function of Ly-6 genes to specifically target those receptor sites, and then we can begin to administer the synthetic compounds and essentially modulate certain pathways in the brain associated with the salient aspects of drug-seeking behaviors,” he said.

Doing so could, for example, alleviate symptoms associated with nicotine withdrawal, such as anxiety and depression, depending on where these receptor subtypes are expressed within the brain.

“It’s unknown what the co-expression patterns are of all these different patterns in Ly-6 genes and where they are in terms of nicotinic receptor expression in the brain,” Dr. George said. “But once we’ve identified those co-localization patterns, we can start to ask questions about the interaction between different Ly-6 genes and different subtypes of nicotinic receptors that may play a role in different types of neurological diseases.”

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