There are several lines of study in the Neurochemistry Laboratory. First, because there is not just one type of nAChR, fundamental work involves identification and classification of the diverse family of nicotinic receptors. Each receptor is defined by its building blocks or constituent subunits. These studies identify subunits and receptor subtypes in different tissues and organ systems, exploit tumor cell lines as factories naturally making nicotinic receptors like those found in normal tissue, or involve creation of genetically engineered cell lines fashioned to examine features of nicotinic receptors suspected or known to exist.
In these studies, techniques from molecular and cellular biology, immunology, protein chemistry, pharmacology, and electrophysiology converge to provide the most comprehensive description of nicotinic receptors possible. For example, identification of differences in the ability of different nicotinic receptor subtypes to interact with specific drugs is used not only to discriminate among receptor subtypes but also to discover new drugs that are selective or specific in their preference for a given receptor subtype. This creates the opportunity to find a nicotine-like drug that could elevate mood by acting at one receptor subtype without causing nicotine dependence through interactions with receptors in the pleasure-reward center of the brain.
Work is continuing to define which of the 17 subunits identified to date combine to make unique receptor subtypes, and features if every subtype identified then need to be characterized. Studies of the effects of chronic nicotine exposure on receptor numbers and function are underway to define how the brain changes in response. Fundamental features of nicotinic receptors in pleasure-reward, emotional, and attention centers are being studied.
Studies extend beyond muscle and nerve cells. For example, evidence suggests that nicotinic receptors are in blood vessels in many organs, including the brain, where they contribute to formation of the blood-brain barrier and influence cytotoxic and vasogenic phases of edema during stroke. Other studies concern the roles of nicotinic receptors in interactions between the nervous and immune systems and in lung or lung tumor growth. Bone formation and reproductive organ function also seem to be influenced by nicotine exposure, implying that nicotinic receptors are found on the relevant cell types.
Nicotinic receptors can be used as models to test new techniques and to push biotechnological horizons. For example, we are evaluating nicotinic receptors as models for the development of sophisticated tools for proteomics research. Genetically engineered cells and site-directed mutagenesis studies are being conducted not only to define structure-function relationships for the many interesting domains in nicotinic receptors, but also as models of genetically based neurological diseases and for studies to define the functional consequences of such mutations.
Our work has revealed nicotinic receptor subunit gene polymorphisms, which may prove to be indicators—assessable through gene-array techniques—of susceptibility to neurological or psychiatric disease or to nicotine dependence and the likelihood of success in smoking cessation therapy. Conversely, other studies have revealed changes in gene activity induced by nicotine exposure, possibly revealing how some effects of nicotine exposure can be long-lasting but also revealing important targets for normal signaling through nicotinic receptors.
Neurochemistry Research Laboratory Accomplishments
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Demonstrating recognition for our work nationally and internationally, past or current funded studies and/or studies leading to published contributions involve dozens of collaborating scientists at the University of Arizona, Arizona State University, Sun Health Research Institute; several state, national, or international biotechnology companies; and at many institutions in the country and worldwide. Co-workers are in cities including Phoenix, Tempe, Tucson, Scottsdale, Sun City, Ann Arbor, Baltimore, Bethesda, Boston, Denver, Durham, Gainesville, Houston, Ithaca, Kalamazoo, Lubbock, Los Angeles, Memphis, Palo Alto, Philadelphia, Raleigh, Richmond, Salt Lake City, San Diego, St. Louis, Tampa and Winston-Salem, Bahia Blanca, Bath, Edinburgh, Edmonton, Geneva, Heidelberg, Montpellier, Oxford, Paris, and San Juan.
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Visiting foreign national scientists, faculty doing sabbatical work, and educators doing summer research projects have been active in our laboratory.
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Contributed to demonstration of the diversity of nAChR
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Identified or created natural or genetically engineered cell models for nicotinic receptor research
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Contributed to basic pharmacological and structural characterization of nicotinic receptors
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Identification using gene chip microarrays of genes regulated by nicotinic receptor activity
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Definition, at the molecular level, of effects that occur with smoking and of chronic nicotine exposure on nicotinic receptor function
