New compound may act to keep thyroid activity in check

05/14/04

OHSU study finds T1 amine rapidly causes hypothermia, blood pressure drop, slow pulse

PORTLAND, Ore. Researchers have isolated a naturally occurring, thyroid hormone-derived compound that produces an inactive, torpid-like state in rodents and could someday help doctors stabilize surgical and trauma patients.

Although the compound, 3-iodothyronamine T1 amine, for short is a derivative of thyroxine, an essential thyroid hormone that influences development, body temperature, metabolic rate and cardiac performance, it has the opposite effect of thyroxine, according to a study by scientists at Oregon Health & Science University, the University of California, San Francisco (UCSF) and Universita di Pisa, Italy.

The new findings suggest that T1 amine affects several organ systems. Consequently, if its molecular and cellular actions can be precisely described, physicians will be in a better position to treat a variety of cardiovascular and endocrine diseases, as well as mental health disorders, said David Grandy, Ph.D., associate professor of physiology and pharmacology, and cell and developmental biology in the OHSU School of Medicine.

"Here we thought we knew thyroid hormone so well, only to find out there's this whole new aspect of it," said Grandy, co-author of a study published in today's online edition of the journal Nature Medicine. T1 amine's "normal function in the body may be to counteract, or keep in check, thyroid hormone's actions."

In mice, T1 amine can induce profound hypothermia, slow heart rate and drop blood pressure, suggesting that it, or related molecules, might provide a valuable new means by which physicians can stabilize patients during surgery and trauma, Grandy said. Within minutes of administering T1 amine, mice appear to go into a "hypometabolic state."

"Although they're inactive and appear to be unmotivated, they definitely are not anesthetized. It almost looks like they're playing dead and have stopped responding to their environment," Grandy said.

T1 amine has a "profound" effect on the heart where it "almost immediately causes a dramatic decrease in pumping and outflow," Grandy said.

Linda Lester, M.D., assistant professor of medicine in the Division of Endocrinology, Diabetes and Clinical Nutrition, OHSU School of Medicine, said physicians have limited means to rapidly reverse the effects of diseases that increase metabolism.

"The compound described in this article could provide a new tool to manage patients in acute hypermetabolic states, including hyperthyroidism," she said. "The effectiveness of this compound in humans would have to be established prior to considering it as a new therapy, but the rodent studies described in this article support further evaluation."

The molecule's structure, its potency and speed of action suggest that it is a previously undiscovered neurotransmitter, said Thomas Scanlan, Ph.D., co-author on the paper and professor of pharmaceutical chemistry and cellular and molecular pharmacology at UCSF. "While changes in hormone levels may take a day to have their effect, neurotransmitters can act within minutes to hours," Scanlan said. "T1 amine acts this quickly, and it has a chemical structure similar to dopamine or serotonin. Since it looks like a neurotransmitter and acts like a neurotransmitter, we hypothesize that it is a neurotransmitter."

Scanlan, an expert on thyroid hormone chemistry and pharmacology, synthesized T1 amine. The researchers at OHSU and UCSF then found that the compound occurs naturally in the brains of rats and guinea pigs, and subsequently in the brains, heart, liver and blood of adult mice.

The prediction and ultimate discovery of T1 amine followed on the heels of a previous discovery made in the Grandy laboratory.

"For us, when we find a new receptor that is made by the body, it means there must be a naturally occurring molecule, or key, that turns it on," Grandy said. "In our efforts to find this receptor's natural key, or ligand, we tested hundreds of compounds. This analysis identified a small set of chemical groups that were important. Our interest turned to thyroid hormone because it contains each of these chemical groups following a simple chemical modification. What we couldn't know ahead of time is that T1 amine would be the best fitting key for our trace amine receptor."

The Grandy lab also was surprised to find that T1 amine's effects on the body were opposite to those associated with thyroid hormone.

Promoting close collaborations between chemists and biologists, like that between researchers at OHSU and UCSF, is a central aim of OHSU's chemical biology initiative, a developing program led by the Department of Physiology and Pharmacology that is to be housed in new research space now under construction on Marquam Hill.

"The program will bring together, on one campus, chemists and biologists who have the common aim of discovering small molecules that are potent regulators of biological processes and, maybe, prototypes for drugs," said David Dawson, Ph.D., professor of physiology and pharmacology, and department chairman.

Demonstrating that T1 amine and the trace amine receptor "talk to one another" may help scientists better understand and treat depression, schizophrenia, movement disorders, obesity, trauma, stroke, diabetes and cardiovascular disease, Grandy said.

Now that the T1 amine compound has been found, and its biological effects observed, Grandy hopes to study its possible connections to drug dependency and other mental health disorders.

"Interestingly, amphetamines and Ecstasy turn this receptor on," he said. "I'd like to think one direction that future studies will take addresses whether or not T1 amine might influence drug-taking behavior."

Other study collaborators included: Katherine Suchland, Paul Kruzich, Dane Crossley II and James Bunzow, Department of Physiology and Pharmacology, OHSU; Matthew Hart, Department of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, UCSF; Grazia Chiellini, Sabina Frascarelli, Simonetta Ronca-Testoni, Riccardo Zucchi, Dipartimento di Scienze dell'Uomo e dell'Ambiente, Sezione di Biochimica, Universita di Pisa, Italy; Yong Huang and Emil Lin, Department of Biopharmaceutical Sciences, UCSF; and Daniel Hatton, Department of Behavioral Neuroscience, OHSU.

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