Identification of receptor could lead to new stroke medications

San Antonio (Dec. 21, 2004) – Chances are when we think of calcium, we think of vitamin D, milk and strong bones. In fact, the adult body contains approximately 1,200 grams (2.6 pounds) of calcium, but not all of it is where we think or does what we think.

Researchers at The University of Texas Health Science Center at San Antonio have discovered a promising way to regulate calcium in brain cells – an important finding considering that high amounts of calcium flood these cells when a stroke occurs. Development of a medication to regulate calcium levels after a stroke might save many neurons from dying and decrease the amount of permanent damage caused by the stroke.

The study was reported Dec. 6 in the Journal of Cell Biology. An introduction to the article is atwww.jcb.org/cgi/content/full/167/5/805-a.

“More than 99 percent of the calcium in our bodies is immobilized in the bones and teeth,” said study co-author Patricia Camacho, Ph.D., associate professor of physiology at the Health Science Center. “Less than 10 milligrams escapes mineralization and is found in circulating fluids and the extracellular environment. A miniscule fraction of this calcium penetrates cells in a controlled fashion. Inside them it plays a critical role as a messenger controlling several functions such as activation of genes, contraction in muscle cells, or secretion in endocrine cells or in the brain. Large quantities of calcium inside a cell cause damage to it.”

The researchers found that proteins called thyroid hormone receptors can activate energy production by cellular mitochondria within short periods of time (seconds to minute time scale). This observation of a fast response contrasts what was believed about thyroid hormone receptors – that they only worked by activating genes, a process that takes hours to days. Mitochondria are the equivalent to power plants in our cells, storing and releasing energy as needed for the body’s metabolic processes. One type of thyroid hormone receptor demonstrated the ability to jump-start these energy factories by sequestering calcium into mitochondria. At the same time, the receptor also regulated the amount of calcium in the cell’s semi-fluid expanse.

Enzymes involved in energy production depend on calcium for their action. This is the first mitochondrial thyroid hormone receptor to be discovered that acts in such a short fashion to produce an energy burst.

“Clearly, the identification of a mitochondrial receptor for thyroid hormone-induced increases in metabolism offers a new pharmacological target from which it will be possible to regulate a broad range of physiological and pathological processes,” said the study’s lead investigator, James D. Lechleiter, Ph.D., professor of cellular and structural biology. “This could lead to new medications that protect cells under conditions of stress.”

Drs. Lechleiter, Camacho and co-authors Drs. Nuttawut Saelim and Linu John are listed as inventors on a U.S. provisional patent titled “Modulation of Metabolism and Calcium Signaling by Mitochondrial Thyroid Hormone Receptors.” The Health Science Center’s office of technology ventures filed the patent.
“The patent is designed to cover any drug that provides therapeutic value through the mitochondrial thyroid hormone receptor,” Dr. Lechleiter said.



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