Gary Lester Stiles
Adjunct Professor in the Department of Medicine
Description of Major Research Interests. This laboratory is dedicated to the understanding of the structure, function and regulation of adenosine receptor systems. These receptors are important in mediating a variety of physiologic effects including changes in heart rate and contractility, blood vessel dilatation, suppression of neurotransmitter release, lipolysis inhibition of platelet function and many others. Until recently, there were only two types of adenosine receptors known; but, recently through the techniques of cloning, a variety of new receptor ubtypes have been found. In addition, it is clear that these receptors couple to a variety of second messenger systems including cAMP, potassium channels, calcium channels and phospholipase C. Studies seek to understand the structure of the receptors, how they transmit the signal across the cell membrane and how they are reulated by a variety of pathphysiologic conditions. In addition, new receptor subtypes are being sought through the technique of a polymerase chainreaction. Deatiled studies on the building site within the receptor for agonists and antagonists are currently underway using recombinant DNA techniques including site-directed mutagenesis and creation of kimeric receptors.
Accomplishments Over the Past year. The laboratory has continued to probe the mechanisms by which the phenomenon of desensitization occurs in a variety of adenosine receptors. Specifically, we have documented that there is a short stretch of amino acids in the carboxyl terminal tail of the A2 adenosine receptor which upon phosphorylation mediates the desensitization of the A2a mediated stimulation of adenylate cyclase. This was very interesting because there are multiple phosphorylation sites within the very long carboxyl terminal tail of the A2 adenosine receptors but most of these are irrelevant for the function of the receptor or the desensitization of the receptor. It is only a single specific amino acid which must be phosphorylated to lead to short-term desensitization. In addition, long-term desensitization occurs even though this short-term desensitization is completely blocked. The newly discovered adenosine receptor, the A3 adenosine receptor, was found to produce multiple effects on adenylyl cyclase following chronic activation by adenosine analogs. Specifically, this receptor can be become down-regulated uncoupled from the G proteins and produce a differential regulation of the Gi class inhibitory proteins. It is also fascinating that the human A3 receptor regulates a different repertoire of Gi proteins than does the rat A3. The mechanism for this differential regulation is currently under investigation. Also, importantly, we were able to demonstrate that a single-stranded DNA binding site in the human A1 adenosine receptor gene promoter is important in activation of this gene. This site is a non-classical activator of genes and addtional work will be required to understand which transcriptional factors bind to this specific site.
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Education, Training, & Certifications
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