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Dianne M. Perez
Assistant Staff

Department of Molecular Cardiology
Lerner Research Institute / NB50
9500 Euclid Avenue
Cleveland, Ohio 44195
Telephone : (216) 444-2058
Fax : (216) 444-9263
perezd@ccf.org

Area of general research interest:

Structure-Function and Mechanistic Studies of Adrenergic Receptors

Current program:

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. This will ultimately lead to the rational design of selective therapeutic agents, a project and goal done in collaboration with Glaxo Wellcome, Inc.

Studies are underway to explore the mechanism of signal transduction in a1-adrenergic receptors. It is thought that agonist-activation imparts conformational movements in the transmembrane spanning domains that transduces a signal to the G-protein. We have shown that a constraining salt-bridge holds the receptor in the inactive state. The docking of the agonist would break the salt-bridge which allows the receptor to adopt the active conformation. This mechanism might be universal with other receptors that bind biogenic amines.

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 similiar mutations in a1-adrenergic receptors can lead to disease states.

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