Lukas - Whiteaker Laboratory

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Lukas-Whiteaker Laboratory


Ronald J. Lukas, PhD
Professor, Division of Neurobiology
Director, Laboratory of Neurochemistry
Vice President of Research
St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute Development Laboratory

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Nicotinic Acetylcholine Receptors in Health and Disease

Every Breath, Every Move,
Every Thought, Every Mood
                © R.J. Lukas

Movement, respiration, emotion, and thought are just a few of the essential but complex processes that result from cascades of chemical signals in the brain and/or body. Work in the Laboratory of Neurochemistry at Barrow Neurological Institute principally concerns nicotinic acetylcholine receptors (nAChR), which are critically involved in this signaling process.

Nicotinic acetylcholine receptors act throughout the brain and body as "molecular switches" that connect nerve cell circuits involved in essential functions ranging from vision and memory to the control of heart rate and muscle movement. nAChR also modulate the release of neurotransmitters and other types of signaling molecules, further demonstrating their influence on brain and body function. Defects in nAChR or their loss can cause diseases such as myasthenia gravis and epilepsy, and nAChR have been implicated in a wide variety of other disorders including Alzheimer’s disease, Parkinson’s disease, schizophrenia, pain, depression, anxiety, and attention deficit disorder. They have also been theorized to play a role in immune and inflammatory disorders.

Nicotinic acetylcholine receptors are also the principal targets of nicotine found in tobacco. The influence of on nAChR contributes to nicotine dependence, nicotine addiction, and perhaps increased susceptibility to certain diseases. At the same time, nicotine dependence can be viewed as a form of self medication to treat depression, anxiety, attention difficulty, and pain.

Studies in the Laboratory of Neurochemistry have shown that nAChR exist as a family of diverse subtypes, each with distinctive drug-binding and functional properties, and each having distinctive subunit compositions. We have advocated for the use of cell lines as experimental models to simplify studies of the diverse nAChR subtypes. We also have helped and continue to assist in developing new and improved techniques for the study of nAChR.

Homology model for assembled, nAChR alpha7 subunit N-terminal extracellular domains as viewed from the side.
Given their broad distribution and physiological relevance, nAChR are ideal targets for regulation of brain and body function. Our work has shown that the number and function of diverse nAChR subtypes can be influenced by many biologically active substances, from steroids to local anesthetics. Furthermore, we have shown they can be influenced by agents acting on the extracellular matrix, the cytoskeleton, on second messenger signaling, and at the nucleus. Nicotine exposure alters the level of expression of nAChR, increasing the number of binding sites while simultaneously decreasing the level of nAChR function via processes that could substantially contribute to nicotine dependence. It is possible that this disabling of nAChR also disables electrical and chemical signaling in neurons or other cell types, thereby accounting for the pharmacological effects of nicotine exposure.

We continue to advance a diverse and multidisciplinary program of research that focuses on nicotinic signaling, employing human tumor cell lines as models for the study of nicotinic receptor properties and as genetically engineered hosts for heterologous expression of a wide range of nicotinic receptor subtypes. In addition, we use molecular, cellular, biophysical, pharmacological, physiological, human, and research animal tissue studies to establish structure and function of nicotinic receptors with a goal of understanding molecular mechanisms involved in nicotine dependence. We also hope to elucidate the role of nicotinic receptors in health and disease, to describe the natural distribution of specific receptor subtypes, and to advance therapeutic drug discovery efforts for disorders such as Alzheimer's disease, depression, attention deficit disorders, and autoimmune diseases.

 

Contact Information

Ronald J. Lukas, PhD
Professor, Division of Neurobiology
Director, Laboratory of Neurochemistry
Vice President of Research
St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute Development Laboratory

Division of Neurobiology
Barrow Neurological Institute
350 West Thomas Road
Phoenix, AZ 85013

Phone: (602) 406-3300
Fax: (602) 406-4172
E-mail: rlukas@dignityhealth.org

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Barrow Neurological Institute
350 W. Thomas Road
Phoenix, AZ 85013
(602) 406-3000