Alcohol use disorders are common and incur a huge cost to society. Unfortunately, pharmacotherapy of alcohol use disorders is restricted to three FDA approved drugs: disulfuram, naltrexone, and acamprosate. Therefore, there is considerable need for the development of new agents to treat these disorders. Mounting evidence suggests that protein kinase C epsilon (PKC?) is a good target for development of drugs to treat alcohol use disorders, based mainly on studies using gene-targeted mice that lack this enzyme (Prkce-/- mice). These mice drink substantially less ethanol than wild type mice, show heightened aversion to ethanol, are more easily intoxicated by low doses of ethanol, and recover from intoxication very slowly compared with wild type mice. These behaviors are associated with enhanced function of GABAA receptors, which are the major mediators of inhibitory neurotransmission in the nervous system. PKC? regulates GABAA receptors by phosphorylating GABAA2 subunits at Ser-327, which reduces their sensitivity to benzodiazepines and ethanol. PKC? also phosphorylates the N-ethylmaleimide sensitive factor (NSF), at Ser-460 and Thr-461, which stimulates removal of GABAA receptors from synapses. The long-term goal of this project is to identify targets for the development of new drugs to treat alcohol use disorders. The objective of this application is to specifically validate PKC? as a drug target and identify additional drug targets within neuronal PKC? signaling pathways. The main hypothesis to be tested is that selective inhibitors of PKC? signaling can reduce voluntary ethanol consumption in mice.
Three aims are proposed.
The first aim will determine the consequences of administering a highly selective PKC? inhibitor and validate PKC? as a drug target to decrease alcohol consumption. This will be achieved by using a new line of mutant mice in which the ATP binding pocket of PKC? has been modified to allow highly specific inhibition by small molecules that do not inhibit native kinases. In the second aim, three novel, related compounds that are potent inhibitors of PKC? will be administered to wild type mice to determine if this class of compounds should be developed further as drugs to treat alcohol use disorders.
The third aim will use a newly developed proteomics approach to identify direct substrates of PKC? for study of their role in regulating GABAA receptors and behavioral responses to ethanol. Because of its focus on identifying new drug targets and pharmacological agents to treat alcohol use disorders, this project has high translational value for serving public health.

Public Health Relevance

Alcohol use disorders are extremely common and very costly to society. There are few therapeutic options available to treat afflicted persons. The studies outlined in this proposal will serve the public health by providing important information that can be used to develop inhibitors of the enzyme protein kinase C epsilon as safe and effective treatments.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
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University of Texas Austin
Schools of Pharmacy
United States
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Blasio, Angelo; Wang, Jingyi; Wang, Dan et al. (2018) Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice. Biol Psychiatry 84:193-201
Pomrenze, Matthew B; Fetterly, Tracy L; Winder, Danny G et al. (2017) The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target? Alcohol Clin Exp Res 41:1986-1999
Maiya, Rajani; McMahon, Thomas; Wang, Dan et al. (2016) Selective chemical genetic inhibition of protein kinase C epsilon reduces ethanol consumption in mice. Neuropharmacology 107:40-48
Blasio, Angelo; Messing, Robert O (2016) Binge Drinking With Protein Kinase C Epsilon: A Role for Mammalian Target of Rapamycin Complex 2? Biol Psychiatry 79:425-6
Pomrenze, Matthew B; Millan, E Zayra; Hopf, F Woodward et al. (2015) A Transgenic Rat for Investigating the Anatomy and Function of Corticotrophin Releasing Factor Circuits. Front Neurosci 9:487
Schuster, D J; Metcalf, M D; Kitto, K F et al. (2015) Ligand requirements for involvement of PKC? in synergistic analgesic interactions between spinal ? and ? opioid receptors. Br J Pharmacol 172:642-53
Lee, A M; Wu, D-F; Dadgar, J et al. (2015) PKC? phosphorylates ?4?2 nicotinic ACh receptors and promotes recovery from desensitization. Br J Pharmacol 172:4430-41
Trudell, James R; Messing, Robert O; Mayfield, Jody et al. (2014) Alcohol dependence: molecular and behavioral evidence. Trends Pharmacol Sci 35:317-23
Jee, C; Lee, J; Lim, J P et al. (2013) SEB-3, a CRF receptor-like GPCR, regulates locomotor activity states, stress responses and ethanol tolerance in Caenorhabditis elegans. Genes Brain Behav 12:250-62
Schuster, Daniel J; Kitto, Kelley F; Overland, Aaron C et al. (2013) Protein kinase C? is required for spinal analgesic synergy between delta opioid and alpha-2A adrenergic receptor agonist pairs. J Neurosci 33:13538-46

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