Divergent behavioral roles of angiotensin receptor intracellular signaling cascades

Mar 23 2006

Researchers at the University at Buffalo and the University of Pennsylvania were the first to demonstrate that two intracellular events, both stimulated by the same cell receptor, can provoke different behaviors in mammals.

The broad implication of the findings may alter the way behavioral neuroscientists think about sub-cellular underpinnings of mammalian behavior, according to the researchers.

The study, "Divergent Behavioral Roles of Angiotensin Receptor Intracellular Signaling Cascades," was published in the journal Endocrinology (Vol. 146, No. 12).

The co-authors of the study are Derek Daniels, assistant professor of psychology at the University at Buffalo, and Daniel K. Yee, research associate professor, Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine.

Daniels says, "The research highlights the importance of intracellular events in the regulation of behavioral states and provides new information about the means through which a single hormone can influence multiple mammalian behaviors like learning and memory, eating, drinking, reproduction and social interaction."

The study examines intracellular signaling pathways stimulated by AT1, a receptor for angiotensin, a polypeptide hormone that regulates internal equilibrium among body fluids.

By using drugs to effect these neural signaling pathways in animal subjects, the team was able manipulate this equilibrium, a finding that Daniels says provides a better understanding of the regulation of blood pressure, and body fluid composition, and could lead to new strategies for treating cardiovascular diseases.

The study of intracellular events in the field of behavioral neuroscience has blossomed over the past 20 years as a result of increased NIH funding for neuroscience research and general strides in molecular biology and technology that permit scientists to examine exactly how cells function at the molecular level.

Daniels explains that the kidneys and lungs produce enzymes that eventually provoke production of angiotensin. It previously was known that angiotensin has robust behavioral effects on animals, causing them to drink water and consume salt. It was also known that angiotensin acts on the surface of cells by binding to receptor molecules, which, in turn, activate proteins and small molecules inside the cells that form "signaling pathways" to cause further cellular changes.

"In our study," he says, "we wanted to examine the connection between these intracellular changes and behavior by looking at the function of two particular signaling pathways that are activated by the receptor for angiotensin."

"We gave the animals a drug that bound the AT1 receptor and activated one signaling pathway, which activates a protein inside the cell called MAP kinase, but didn't activate another pathway, which increases levels of something called IP3 inside the cell," Daniels says. "Surprisingly, the animals given this drug increased their salt intake without increasing their water intake.

"This supports our hypothesis that intracellular signaling pathways stimulated by the activation of angiotensin receptors can be separated based on behavioral relevance," he says, "something that had not been shown before."

"Understanding how signaling pathways work to regulate the ingestion of water and salt may shed light on how similar events affect other behaviors, including learning and memory, feeding, reproduction and social interactions. Daniels says the regulation of behavioral states by angiotensin "is a well-studied problem that has provided a wealth of information about the interface between peripheral hormones and central control of behavior.

"A good deal of attention had been paid to the intracellular signaling pathways under the control of the receptors for angiotensin," he says, "but our research makes strides toward understanding how these processes mechanistically affect behavior."

Daniels's research in behavioral neuroscience focuses on the genomic and neural substrates of ingestive behaviors critical for the maintenance of body-fluid, cardiovascular and energy homeostasis. Specific areas of interest include the neural circuits that contribute to these behaviors and the intracellular events that occur at various nodes within the circuits pathways.

In addition to the publication of this study in Endocrinology, his work has been published in journals such as the Journal of Neuroscience, Brain Research, Hormones and Behavior, Neuroscience Letters, Peptides, Physiology and Behavior and the Journal of Neurobiology.

http://www.buffalo.edu