Nicotinic Acetylocholine Receptors in Health and Disease
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Every Breath, Every Move,
Every Thought, Every Mood
© R.J. Lukas, Ph.D.
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, body, or both. Work in the Laboratory of Neurochemistry at the Barrow Neurological Institute principally concerns molecules critically involved in such signaling called nicotinic acetylcholine receptors (nAChR).
nAChR act throughout the brain and body as "molecular switches" to connect nerve cell circuits involved in essential functions ranging from vision and memory to the control of heart rate and muscle movement. Defects in nAChR or their loss causes diseases such as myasthenia gravis and epilepsy and can contribute to Alzheimer's disease, Parkinson's disease, and schizophrenia.
nAChR are also the principal targets of tobacco nicotine. Effects on nAChR contribute to nicotine dependence, the drive to use tobacco products, and perhaps increased susceptibility to many diseases. On the other hand, nicotine-like medicines show promise in the treatment of diseases such as attention deficit/hyperactivity disorder (ADHD) and Tourette's syndrome and in alleviation of anxiety, pain, and depression, suggesting involvement of nAChR in both psychiatric and neurological disorders.
Studies in the Laboratory of Neurochemistry have helped to show that nAChR exist as a family of diverse subtypes, each with distinctive drug-binding and functional properties, and each comosed of distinctive subunits. We have championed the use of cell lines as experimental models to simplify studies of diverse nAChR subtypes. We also have helped and continue to develop new and improved techniques to study nAChR.
Given their broad distribution and physiological relevance, nAChR are ideal targets for regulation of brain and body function. We have shown that numbers and function of diverse nAChR subtypes can be influenced by many biologically active substances, ranging from steroids to local anesthetics and by agents acting on the extracellular matrix, cytoskeleton, second-messenger signaling, and nucleus. We also have shown that chronic exposure to nicotine induces numerical upregulation of many diverse nAChR subtypes via a post-transcriptional process dominated by effects on intracellular pools of receptors or their precursors. Some current studies are testing our hypothesis that chronic exposure to nicotine, as occurs with habitual use of tobacco products, disables nAChR and the nerve cell circuits that they subserve, thereby contributing to long-lasting changes in brain and body function. This hypothesis is based on our observation that chronic exposure to nicotine induces, via a post-transcriptional process that is causally and mechanistically distinct from upregulation, a long-lasting loss of function ("persistent inactivation") of all nAChR subtypes tested.
Other current studies use powerful genetic engineering techniques to create cell lines that express nonhuman or human recombinant nAChR of defined subunit composition. We are using these transfected cells and transgenic nAChR to help identify nAChR subtype-specific or subtype-selective agents and to help direct work to identify therapeutic compounds targeting nAChR that could have positive effects (anxiolytic, analgesic, neuroprotective) with minimal adverse side effects. Some of our genetic engineering studies have shown that expression of certain mutant forms of nAChR are lethal to transfected neurons. This finding is consistent with the idea that aberrant forms or function of nicotinic receptors can cause or contribute to neurological or psychiatric diseases.
Other studies are examining nicotinic receptors in the brain and spinal cord in normal animals and in animal models of neurological disease. Human sensitivity to nicotine and susceptibility to nicotine dependence and tobacco-related or other diseases may be influenced by genetic differences across individuals in nicotinic receptors. We also are identifying potentially informative nAChR subunit gene polymorphisms.
