Summary: Targeting a protein called MUNC13-1 could help reduce tolerance to alcohol and reduce addiction, researchers say.
Source: University of Houston.
A protein in the brain that binds to alcohol could be the key to curing alcoholism, reports UH College of Pharmacy medicinal chemist Joydip Das in eNeuro, a journal of the Society for Neuroscience. The protein, called MUNC 13-1, plays a pivotal role in the development of tolerance to alcoholism according to Das.
“Addiction to alcohol remains one of the most significant mental health problems throughout the world. A major challenge is to understand how ethanol, or alcohol, changes behavior and the brain during the descent into addiction,” Das reported. Developing tolerance is a critical step in that descent.
“If a person becomes tolerant of one drink, he will have another and maybe another. If we could stop alcohol from binding into MUNC 13-1 it will help problem drinkers in reducing tolerance. If we can reduce tolerance we can reduce addiction,” said Das whose study focuses on binge alcohol exposure.
The process of MUNC 13-1 binding to alcohol takes place in a brain synapse, where one nerve cell, or neuron, passes a signal to another. Specifically, the binding takes place in the presynaptic space, a much understudied portion of the synapse mechanism.
During binge alcohol exposure, alcohol creates widespread and long-lasting changes in neural activity, altering both presynaptic and postsynaptic activity.
Thus far the work has been done using the Drosophila genetic model system, which offers a simple model, but various similarities. Their activating protein is called Dunc13, the equivalent to MUNC 13-1.
“Reduction in Dunc13 produces a behavioral and physiological resistance to sedative effects of ethanol,” said Das. That makes MUNC 13-1 an important target for developing drugs. “We need to develop a pill that would inhibit alcohol binding to MUNC 13 and reduce its activity. Based on our results so far, this would likely reduce the formation of tolerance, making it harder to become addicted to alcohol,” said Das.
Source: Laurie Fickman – University of Houston
Publisher: Organized by NeuroscienceNews.com.
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Original Research: Abstract for “Ethanol Regulates Presynaptic Activity and Sedation through Presynaptic Unc13 Proteins in Drosophila” by Shiyu Xu, Satyabrata Pany, Kevin Benny, Khadeeja Tarique, Ola al-Hatem, Kathleen Gajewski, J. Leigh Leasure, Joydip Das and Gregg Roman in eNeuro. Published June 4 2018.
Ethanol Regulates Presynaptic Activity and Sedation through Presynaptic Unc13 Proteins in Drosophila
Ethanol has robust effects on presynaptic activity in many neurons, however, it isn’t yet clear how this drug acts within this compartment to change neural activity, nor the significance of this change on behavior and physiology in vivo. One possible presynaptic effector for ethanol is the Munc13-1 protein. Herein, we show that ethanol binding to the rat Munc13-1 C1 domain, at concentrations consistent with binge exposure, reduces diacylglycerol binding. The inhibition of diacylglycerol binding is predicted to reduce the activity of Munc13-1 and presynaptic release. In Drosophila, we show that sedating concentrations of ethanol significantly reduce synaptic vesicle release in olfactory sensory neurons, while having no significant impact on membrane depolarization and Ca2+ influx into the presynaptic compartment. These data indicate that ethanol targets the active zone in reducing synaptic vesicle exocytosis. Drosophila, haploinsufficent for the Munc13-1 ortholog Dunc13, are more resistant to the effect of ethanol on presynaptic inhibition. Genetically reducing the activity of Dunc13 through mutation or expression of RNAi transgenes also leads to a significant resistance to the sedative effects of ethanol. The neuronal expression of Munc13-1 in heterozygotes for a Dunc13 loss-of-function mutation can largely rescue the ethanol sedation resistance phenotype, indicating a conservation of function between Munc13-1 and Dunc13 in ethanol sedation. Hence, reducing Dunc13 activity leads to naïve physiological and behavioral resistance to sedating concentrations of ethanol. We propose that reducing Dunc13 activity, genetically or pharmacologically by ethanol binding to the C1 domain of Munc13-1/Dunc13, promotes a homeostatic response that leads to ethanol tolerance.
Significance Statement At relatively low concentrations, ethanol inhibits the activity of many presynaptic termini (Liu and Hunt, 1999). Homeostatic changes in presynaptic activity are proposed to underlie the formation of functional tolerance (Koob and Bloom, 1988; Ghezzi and Atkinson, 2011). We do not currently know where ethanol binds to bring about changes in presynaptic activity and homeostasis. We now show that ethanol will bind to the C1 domain of the Munc13-1 protein at intoxicating concentrations and inhibit the binding of diacylglycerol. Reducing the activity of the Drosophila Dunc13 ortholog leads to a homeostatic change that promotes behavioral and physiologic resistance to intoxicating levels of ethanol. Hence, Unc13 proteins are likely sites for ethanol’s action within the presynaptic compartment that bring about tolerance.