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RESEARCHERS DISCOVERING MECHANISM OF BODY'S 'OFF SWITCHES'

RESEARCHERS DISCOVERING MECHANISM OF BODY'S 'OFF SWITCHES'
     DURHAM, N.C., Sept. 30 /PRNewswire/ -- A team of biochemists has reported new insights into central components of what may be some of the body's most important biochemical "off switches."
    Although their research is basic, the researchers say these and other newly reported findings may mark progress toward improved drug treatments for a variety of human illnesses.
    The switches -- consisting of enzymes called BARKs ("beta - A - R - K") and another protein, Barrestin ("beta - arrestin") -- quickly shut down activated receptors in the body to prevent them from running out of control.  Receptors are molecules on the surface of living cells that switch on cell activity when triggered by hormones or drugs.
    The BARK/Barrestin system may naturally regulate a wide range of body processes, theorize the scientists.  For example, such switches may play important roles in regulating vision, smell, emotions and blood pressure.
    However, the BARK/Barrestin system may also rapidly desensitize the action of drugs used to treat heart disease and other ailments, said the scientists.  Thus, learning how to selectively shut down the BARK/Barrestin system might allow physicians to administer far smaller amounts of drugs and still enhance their effectiveness.
    The latest research paper by researchers at the Duke University Medical Center and the Johns Hopkins University School of Medicine will be published Thursday (Oct. 1) in the October Journal of Neuroscience.
    In that paper, the researchers report discovering that the two known kinds of BARK -- BARK1 and BARK2 -- are found throughout the brain. They also report finding different concentrations of BARK1 and BARK2 in different places in the brain.
    Related discoveries about BARK and Barrestin have also been reported in recent issues of Science, Nature and the Journal of Biological Chemistry.
    Authors of the Journal of Neuroscience paper are Jeffrey Arriza, Marc Caron and Robert Lefkowitz of the Howard Hughes Medical Research Institute at the Duke University Medical Center; Ted Dawson, Lee Martin and Solomon Snyder of the Johns Hopkins School of Medicine; and Richard Simerly of the Oregon Regional Primate Center.
    The BARK enzyme -- BETA Adrenergic Receptor Kinase -- was discovered six years ago by Lefkowitz and his colleagues at Duke.  They found that the enzyme selectively deactivates certain receptors, called beta adrenergic receptors, on the cell surface that had been activated by adrenaline or other drugs.  They later discovered that another protein "cofactor," Barrestin, was necessary for BARK to work.
    Among other actions, adrenergic receptors control heart rate, blood pressure and respiration.  Such effects are part of the receptors' overall action to turn on the body's "alarm" mechanism, preparing the body to cope with danger.
    Similar receptors, all of which are called "G-protein-coupled receptors," are found throughout the body, triggering mechanisms of sight, smell, taste, and transmission of nerve impulses in the brain and nervous system.  All such receptors work by activating a three-part molecule known as a G-protein, which then splits, with one subunit turning on the cell's activity.
    In a Sept. 5 paper in the Journal of Biological Chemistry, researchers led by Duke Medical Center's Havard Attramadal, Caron and Lefkowitz also reported discovering a new form of Barrestin, called Barrestin2.  They detected the two forms of Barrestin throughout the brain.
    According to Lefkowitz, the newly reported discoveries hint that the BARK/Barrestin mechanism may represent an intricate control system for many kinds of receptors throughout the body.
    "We found BARK and Barrestin distributed much more widely throughout the mammalian brain than could possibly be accounted for by their actions being limited to the beta adrenergic receptor," he said.
    Of the discovery of Barrestin2, he said:
    "Our supposition is that there are additional forms of both BARK and Barrestin.  Maybe different classes of receptors are acted on by different BARKs and Barrestins, and there'll be some organizing principles.  But we haven't a clue as to what those organizing principles are yet."
    In the Sept. 10 Nature and the Aug. 28 Science, the Duke Medical Center scientists, including James Inglese, Walter Koch, Julie Pitcher and Patrick Casey, also reported significant details of how BARK works.
    In the Science paper, they reported finding that a subunit that has split from the G-protein pulls, or "translocates," BARK to the membrane, helping to shut down the activated receptors.  Until recently, this subunit, called the beta-gamma subunit, was not thought to have a significant role in the cell's regulatory machinery.  By contrast, the alpha subunit is the one that activates the cell.
    But now, said Lefkowitz, research from several laboratories, including Duke, indicated that the beta-gamma subunit plays many previously unappreciated roles.  The beta-gamma subunit carries a sort of molecular "grappling hook" that it uses to attach to the cell membrane.  BARK lacks this grappling hook, called an isoprenoid, so the only way it can reach its receptor target is to be carried by the beta- gamma subunit.
    "It's a perfect example of a feedback regulatory system," said Lefkowitz.  "When the receptor is activated, that's when the beta-gamma is freed up from alpha.  So even as the alpha subunit is activating the cell, the beta-gamma subunit is binding to BARK and pulling it in to turn the whole thing off.
    "From the point of view of drug development, this is another potential place we can try to block drug desensitization," he said.
    The Duke and Johns Hopkins research is supported by the National Institutes of Health and the American Cancer Society.  Lefkowitz and Caron are Howard Hughes Medical Institute investigators.  Lefkowitz is the recipient of the 1992 Bristol-Myers Squibb award for Distinguished Achievement in Cardiovascular Research.  Earlier this month, he was also awarded the Giovanni Lorenzini Foundation Prize for Basic Biomedical Research.
    -0-             09/30/92
    CONTACT:  Dennis Meredith of Duke, 919-681-8054, or home, 919-490-6740; or Rachel Wilder of Johns Hopkins, 410-955-8725 CO:  DUKE UNIVERSITY IN:  MTC ST:  NC -- NY044 -- X786  09/30/92
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