A University of Houston College of Pharmacy researcher is characterizing a potential therapeutic target to increase heart function following a heart attack, helping alleviate the symptoms of heart failure.
The National Heart, Lung, and Blood Institute awarded $459,000 to associate professor of pharmacology Bradley K. McConnell to do the work which involves the actions of adrenaline/noradrenaline on the heart. They are also known as catecholamines, the “fight-or-flight” response hormones.
“The release of catecholamines is a normal and acute occurrence if you’re needing to run a marathon or escape an attack, for instance, but in heart failure it is no longer acute, it becomes a chronic response. Every day for the rest of your life those hormones will be elevated above normal levels,” said McConnell. “Once this happens, this elevated response desensitizes receptors on the cells of the heart.”
Catecholamines are released and bind to the β-adrenergic receptor (β-AR) located on the cells of the heart. β-AR signaling is the primary mechanism to increase the ability of the heart to contract or pump blood. However, chronic β-AR stimulation, which occurs in heart failure, results in reduced contractility due to desensitization of these receptors and thus the heart is no longer able to respond to the demands of the body.
The receptors, once able to bind to the hormones, respond to the overstimulation of the continual adrenaline rush on them by desensitizing, or retracting into the cell itself. If the receptor is no longer there it cannot help respond to the heart’s demands.
“I want to try to identify how to get those receptors to stay on the membrane longer so that even during heart failure we can get those receptors to increase heart function,” said McConnell. He said the key is a protein called gravin, or AKAP12, an A-kinase anchoring protein that fine-tunes cellular responses and interacts with the β-AR subtype, β2-AR, to regulate the expression of this receptor on the cells of the heart, allowing it to bind and respond to the catecholamine’s actions.
“We are working to identify the role of gravin on regulating the expression of receptors on membranes,” said McConnell. “We have preliminary data that without gravin we see a much larger increase of the receptor on the membrane, and the overexpression brings the opposite effect.”
McConnell’s co principal investigator on this project is Preethi Gunaratne, professor of biology and biochemistry.