M.Bannon
Michael J. Bannon, Ph.D. Professor
Wayne State University School of Medicine
540 E Canfield Ave, 3355 Scott Hall
Detroit, MI 48201

Telephone (313) 993-7271
Fax (313) 577-6739

Email:mbannon@med.wayne.edu
RESEARCH INTERESTS:

Dopamine transporter gene: Regulation and role in CNS disorders
The neurotransmitter dopamine (DA) exerts important effects on locomotor activity, motivation and reward, and cognition. The DA transporter (DAT) is a plasma membrane protein expressed exclusively in DA neurons (about 1 of every million neurons in the brain) that clears DA released into the extracellular space, thereby regulating the amplitude and duration of DA signaling. The DAT is also an important target for cocaine and other psychostimulants, DA-selective neurotoxins, as well as some drugs used in the treatment of attention deficit disorder and depression. Our lab has focused on understanding the regulation of DAT gene expression and alterations in DAT function associated with a variety of neuropsychiatric disorders. The armamentarium we employ includes standard cellular and molecular neuroscience techniques, as well as particle-mediated transfection of DA neurons in organotypic culture, the analysis and manipulation of in vivo DAT expression (siRNA, ChIP, etc) and human postmortem analyses.

We’ve identified changes in DAT gene expression associated with the normal human aging process and in Parkinson’s disease. In other experiments, we’ve identified DAT gene sequences contributing to DA cell-specificity of expression using an in vivo transgene delivery system, and employed this strategy to elicit biochemical and functional recovery in an experimental model of Parkinson’s disease.

As mentioned above, the DAT is a critical target for cocaine, and we’ve identified cocaine-induced losses of DAT gene expression in the midbrain DA neurons of human chronic cocaine abusers. Decreased DAT expression is correlated with the decreased expression of nurr1 and pitx3, two transcription factors essential for the development of the midbrain DA phenotype, suggesting that these factors are critical to the maintenance of DAT expression and DA phenotype as well, and that cocaine abuse leads to a diminution of DA phenotype. We are currently investigating the nontraditional cellular mechanism through which nurr1 enhances DAT gene transcription. We’ve also recently discovered that members of the specificity protein (Sp) family of transcription factors are strong trans-activators of DAT gene transcription and that valproate, a drug with a broad spectrum of efficacy in CNS disorders, increases DAT gene expression in an Sp transcription factor-dependent manner. Elucidating the regulation of DAT gene expression may lead to novel therapeutic strategies for stimulant abuse and a wide variety of brain disorders involving dysregulation of the DAT and DA neurotransmission.

Microarray analysis of the addicted human brain
Drug abuse is thought to induce long-term cellular and behavioral adaptations as a result of alterations in gene expression. Understanding the molecular consequences of addiction may contribute to the development of better treatment strategies. Our studies have utilized high throughput microarrays to identify global gene expression changes in the postmortem human nucleus accumbens (the ‘reward center’) of chronic cocaine and heroin abusers. Overall, the profiles of nucleus accumbens gene expression associated with chronic cocaine or heroin abuse are largely unique, despite some common effects of these drugs on DA neurotransmission. We are currently annotating the transcripts changed in drug abusers brains and extending these studies to other brain regions critical to drug addiction, craving and relapse.

Regulator of G protein signaling 9: a potential link between DA and NMDA membrane signaling and nuclear events
Another research area of the lab in recent years has been the study of regulators of G protein signaling (RGSs), molecules that accelerate the GTPase activity of G alpha subunits, thus helping to terminate G protein-mediated signaling events. We’ve focused on the brain-specific splice variant RGS9-2 (which we first cloned and mapped in terms of tissue distribution), uncovering several novel aspects of RGS9-2 biology: First, RGS9-2 exhibits a strong nuclear (as well as cytosolic and plasma membrane-associated) localization in both RGS9-positive neurons and transfected cells. Furthermore, some evidence suggests that nuclear RGS9-2 may directly or indirectly regulate transcription. Second, using yeast two-hybrid and co-immunoprecipitation experiments, we’ve shown that RGS9-2 physically interacts with a mediator of calcium-dependent inactivation to modify this form of NMDA receptor inactivation. The unexpected functional interaction between RGS9-2 and NMDA receptors, combined with our previous findings, begin to suggest a bifunctional role for RGS9-2 as both a participant in membrane signaling and a regulator of nuclear function. This hypothesis is the subject of ongoing studies.  


Current Lab Personnel

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Links:

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