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Dianne M. Perez, Ph.D.Staff
Department of Molecular Cardiology
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Area of general research interest:
Structure-function and Physiological Studies of Adrenergic Receptors
Current program:
- Finding structural determinants of a1-adrenergic subtype selectivity
- Physiology of a1-adrenergic receptor subtypes
- Pathogenesis of a1-constitutive activity
Investigators:
- Huifang Ge, Ph.D.
- Manveen Gupta, Ph.D.
- Robert Papay, B.S.
- Ting Shi, Ph.D.
Collaborators:
- Van Doze, Ph.D., University of North Dakota
- Michael T. Piascik, Ph.D., Department of Pharmacology and the Vascular Biology Research Group, University of Kentucky College of Medicine, Lexington, KY.
Brief Description:
a1-Adrenergic receptors are members of the superfamily of G-protein-coupled receptors (GPCRs) and belong to a smaller group of adrenergic receptors (a1; a2; b) that help to regulate the sympathetic nervous system. They regulate smooth muscle contraction and particularly become important in cardiovascular function during disease states where they become up-regulated such as in myocardial ischemia. Drugs that bind a1-adrenergic receptors are a current treatment for high blood pressure, arrhythmias, angina and is the drug of choice for benign prostatic hypertrophy. However, the mechanism by which these drugs bind and influence receptor function is unknown.
My laboratory is interested in three major areas of research: how ligands bind in adrenergic receptors at the molecular level; the mechanism by which ligands can induce signal transduction; and the receptor's role in physiology and disease states. Towards this end, we have identified several amino acid residues in the receptor that are involved in agonist and antagonist docking in different a1-subtypes. The paradigms of binding seem unique as compared to related receptors.
A second area of study is the use of DNA microarrays to explore potential differences in function of the three a1-AR subtypes. We have found some subtype-specific changes in gene-expression and will explore these differences in physiological settings.
The third area of research is the role of a1-adrenergic receptors in physiology and disease states. In collaborative studies with Dr. Michael Piascik, Director of the Vascular Biology Group at the University of Kentucky, we are exploring where and which a1-subtypes are involved in vascular smooth muscle contraction. These types of studies involve localization and antisense technology. In certain disease states, the a1-subtypes might have undergone somatic point mutations which led to altered function. This hypothesis has precedent with other G-protein-coupled receptors such as the leutinizing hormone and thyrotropin receptors where in vivo point mutations in receptor structure has led to conditions such as precocious puberty and thyroid adenomas, respectively. We are currently using transgenic technology to explore if similar mutations in a1-adrenergic receptors can lead to disease states.
We have recently found that systemic overexpression the a1B-subtype in all naturally occurring tissues causes a neurodegenerative disease called Multiple System Atrophy (MSA). This disease is Parkinsonian-like with dopamine terminal loss in the substantia nigra but the atrophy is also prevalent in the cerebellum and essentially progresses with age to spread to all domains of the brain. This is the first reported animal model for MSA. We are continuing to characterize our model and to determine the mechanism. Since antagonists to the alpha1 receptor seem to improve the symptoms in mice, this work may eventual translate to humans and provide the first therapy for this debilitating disease.
Transgenic mice with GFP tags are localizing the protein expression of these receptors in the brain and other tissues. Since GPCR antibodies are notoriously weak for endogenous detection, these animal models are useful for tracking these receptors in vivo.
Key References:
Yun J, Zuscik MT, Gonzalez-Cabrera P, Ross SA, McCune DF, Piascik MT, and Perez DM. Gene expression profiling of a1b-adrenergic receptor-induced cardiac hypertrophy by oligonucleotide arrays Cardiovascular.Research 57: 443-455, 2003.
Yun J, Gaivin RJ, McCune DF, Atthaporn B, Papay RS, Ying Z, Gonzalez-Cabrera PJ, Najm I, and Perez DM. Gene expression profiles of neurodegeneration induced by the a1b-adrenergic receptor: NMDA/ GABAA dysregulation and apoptosis. Brain 126: 2667-2681, 2003 (cover issue).
Gonzalez-Cabrera PJ, Gaivin R, Yun J, Ross SA, Papay RS, McCune DF, Rorabaugh BR, and Perez DM. Genetic profiling of a1-adrenergic receptor subtypes by oligonucleotide Microarrays: Coupling to IL-6 secretion but differences in STAT 3 phosphorylation and gp-130. Mol. Pharmacol. 63: 1104-1116, 2003.
Ross SA, Rorabaugh B, Chalothorn D, Yun J, Gonzalez-Cabrera PJ, McCune DF, Piascik MT, and Perez DM. The a1-adrenergic Receptor Decreases the Inotropic Response in the Mouse Langendorff Heart Model Cardiovascular Research 60: 598-607, 2003.
Gonzalez-Cabrera PJ, Ting Shi, Yun J, McCune DF, Rorabaugh B, and Perez DM. Differential Regulation of the Cell Cycle by a1-adrenergic Receptor Subtypes. Endocrinology 145: 5157-5167, 2004.
Papay R, Gaivin R, McCune DF, Rorabaugh BR, Macklin WB, JC McGrath, and Perez DM. The a1-adrenergic Receptor is expressed in Neurons and NG2 Oligodendrocytes. J. Comparative Neurology 248:1-10, 2004 (cover issue).
Rorabaugh BR, Ross SA, Gaivin RJ, Papay RS, McCune DF, Simpson PC, and Perez DM. The a1A- but not the a1B-adrenergic Receptor Preconditions the Ischemic Mouse Heart through a staurosporine-sensitive, chelerythrine-insensitive mechanism. Cardiovascular Research 65:436-45 2005.
McCune DF, Gaivin RJ, Rorabaugh BR, and Perez DM. Bulk is a Determinant of Oxymetazoline Affinity for the a1-adrenergic Receptor. Receptors and Channels 10: 109-116, 2004 (cover issue).
Rorabaugh BR, Gaivin RJ, Papay RS, Shi T, Simpson PC, and Perez DM. Both a1A- and a1B-Adrenergic Receptors Cross-talk to Downregulate β1-ARs in Mouse Heart: Coupling to Differential PTX-Sensitive Pathways. J Molecular Cellular Cardiology 39: 777-784, 2005.
Perez D. A mouse model for multiple system atrophy. In LeDoux M, ed. Animal Models of Movement Disorders. Burlington, MA: Elsevier, 2005;585-594.
Shi T, et al. Novel a1-adrenergic receptor signaling pathways: secreted factors and interactions with the extracellular matrix. Mol Pharmacol 2006;70:129-42.
Papay R, Gaivin R, Archana J, McCune DF, McGrath JC, Rodrigo MC, Simpson PC, Doze VA and Perez DM. Localization of the Mouse a1A-Adrenergic Receptor in the Brain: a1A-AR is expressed in Neurons, GABAergic Interneurons and NG2 Oligodendrocyte Progenitors (in press).