Walk to a sink, in a kitchen or a bathroom, and turn on the faucet. Unless the drain is plugged or you have serious plumbing problems, the water is going to flow out of the bottom of the sink, down the drain, and the water won’t rise beyond a certain level.
It turns out that the same thing happens in our body’s cells all the time, with chemicals that act as messengers between different parts of our body. Just as there are sources that produce those chemical messengers, there are drains that whisk away those chemicals after they’ve served their purpose.
Dr. Joseph Beavo, professor of pharmacology at the UW, studies those drains. They’re chemical compounds known as phosphodiesterases, or PDEs, that help get rid of cellular messengers. Beavo will discuss his research on PDEs in this month’s Science in Medicine Lecture.
The basis for the study of PDEs came in the 1960s, when Dr. Earl Sutherland, Jr. proposed his theory that some hormones and other messengers within the body can communicate between cells without ever penetrating the cell wall. That is, they act as first messengers, stopping at the cell wall and transmitting signals to second messengers inside the cell. The first of the second-messenger molecules that Sutherland discovered was cyclic AMP, and he later won the Nobel Prize for his work.
Many scientists began studying how those second messengers inside cells were created, and what regulated their production.
“Our work has focused mostly on the degradation of these second messengers, which it turns out is just as important as their synthesis,” said Beavo.
That’s where PDEs come into the picture. PDEs act on those second messengers by breaking a chemical connection known as phosphodiester bond. When you break that bond, the messenger is inactivated, and it later gets taken up by the body and recycled into other compounds.
But why are PDEs so important? It turns out that being able to control the body’s version of the sink-stopper can be a powerful tool in treating some illnesses. Second messengers like cyclic AMP and cyclic GMP appear all over the body, and play vital roles in processes like vision and light reception, hormone secretion, and the steady beating of the human heart.
If one of those processes is out of balance, then having the ability to control the levels of second messengers in cells can help get the process back to normal. A drug that inhibits PDEs works like putting a stopper into the cell’s drain, and the second messengers build up. That can help restore a cycle that had slowed down or become irregular.
Some of the most high-profile examples of PDE inhibitors are drugs like Viagra, Cialis, and Levitra, which are used to treat erectile dysfunction by allowing cyclic GMP to build up in penile smooth muscle cells, increasing blood flow to the penis.
Another common PDE inhibitor is theophylline, which helps dilate bronchial muscles and open up obstructed breathing pathways in patients with asthma or pulmonary disease.
For many years scientists have done quite a bit of research into PDE inhibitors, and now some researchers are looking at creating PDE activators.
“A PDE activator could work just like a beta blocker for treating heart problems,” said Beavo.
Beta blocker drugs are used to treat heart disease symptoms like high blood pressure and elevated heart rate. They block the action of hormones that speed up heart rate and increase blood pressure. In principle, PDE activators could do much the same thing, by reducing the level of second messengers in heart muscle cells, thereby decreasing the force and rate of the heart beat.
Beavo and his colleagues are looking at new ways to regulate PDEs in the body. One area of research focuses on regulating an individual PDE – one of the several dozen types – in a cell without affecting others in the same cell. They hope to develop drugs that can knock out one or more of the 22 genes that regulate production of the various PDEs.
His group is also using sophisticated techniques, like X-ray crystallography, that can provide images of chemical structures at the molecular level. They hope that by learning more about PDE structure, they can better understand how those compounds that bind to PDEs affect their function.
Beavo will discuss the latest in research on PDEs in the Distinguished Science in Medicine Lecture, titled “Phosphodiesterases: From Lab Bench to Bedside,” which will be held at 1 p.m., Thursday, May 19, in Hogness Auditorium, Room A-420 of the UW Health Sciences Center.