Cell signaling discovery yields heart disease clues

Hughes investigator John Scott long studied signal transduction system

A pulsing heart cell is giving Oregon Health & Science University researchers insight into how it sends and receives signals, and that’s providing clues into how heart disease and other disorders develop.

In a study appearing in today’s edition of Nature, John Scott, Ph.D., a Howard Hughes Medical Institute investigator and senior scientist at OHSU’s Vollum Institute, found that heart muscle cells become enlarged when an intricate intracellular signaling pathway regulated by a messenger molecule called muscle-specific A-kinase anchoring proteins, or mAKAPs, is perturbed.

The cells’ growth, known as cardiomyocyte hypertrophy, can lead to congestive heart failure and other forms of cardiovascular disease, which affect more than 70 million Americans and cause about 1.4 million deaths each year.

A cell communicates with another cell by sending over a messenger molecule, typically a hormone, which activates a secondary regulatory messenger molecule – cyclic AMP (cAMP) – within a particular compartment in the recipient cell. This causes cAMP to stimulate an enzyme that triggers the activity of proteins involved in altering a cell’s physiology and governing other biochemical events. According to Scott, mAKAPs tether the enzyme, called protein kinase A (PKA), to particular locations in the cell.

“Hypertrophy is a fairly good laboratory model for certain forms of heart failure, and the PKA signaling pathway is perturbed in certain cases of heart disease,” said Scott, whose laboratory was the among the first in the world to track AKAP interaction. “That’s why this study may have a high translational and clinical impact.”

According to the study, the mAKAP signaling system has been linked to excessive heart cell enlargement, which increases the potential for heart disease. One technique involves using drugs, such as a growth hormone, to activate a molecule known as ERK5, which suppresses the enzyme phosphodiesterase. This causes cAMP, which is normally metabolized by phosphodiesterase, to accumulate in certain parts of the cell.

“Many, many phosphodiesterases are drug targets,” Scott noted. “So potentially, drugs that could target this particular phosphodiesterase, particularly, could be very useful. That’s still a long way away, but that’s where the work will go. Plus, it fits into a large body of work implicating these molecules as markers for certain forms of heart disease. Heart rate, for example, is controlled by calcium, and there’s some level of regulation by cyclic AMP as well.”

To show the signal transduction process in a heart muscle cell, Scott and his colleagues used a fluorescent microscope that captures protein molecules stained with various colored dyes to show PKA activity in a cell. In one set of images, captured over six minutes, a greenish-yellow ring appears to expand around the cell’s nucleus before quickly shrinking. “That’s showing the rise in PKA activity, and the drop,” Scott said.

Scott compares a cell to a highly organized city containing a variety of organizations serving particular functions, such as fire and police departments, an airport, a city hall and other entities. They all use one communication system, but information is delivered to, and interpreted by, each entity differently.

“The idea is that the cell is like this three-dimensional city, and at different times of the day, different things happen in the city,” he explained. “This family of molecules we work on serves to pinpoint enzymes within three dimensions of the cell, and that’s very important because it means that these enzymes act very locally. What the imaging data in this paper shows is that not only do they work in three dimensions, but there’s this fourth dimension – time.”

In addition, he said, “phosphodiesterase is a great drug target that could be something of importance in terms of pharmaceutical intervention at a later date.”