Researchers have modified a honeybee venom toxin so that it can be used as a tool to study the inner workings of ion channels that control heart rate and the recycling of salt in kidneys.

In general, ion channels selectively allow the passage of small ions such as sodium, potassium, or calcium into and out of the cell.

The study, published in the Proceedings of the National Academy of Sciences, is from the laboratory of Zhe Lu, M.D, Ph.D., Professor of Physiology and a Howard Hughes Medical Institute Investigator, who looked at the action of a natural bee toxin on inward-rectifier potassium channels, Kir channels for short, to identify new approaches to treat cardiovascular disease.

The honeybee venom toxin, called tertiapin, or TPN, stops the flow of potassium ions across cell membranes by plugging up the opening of Kir channels on the outside of cells. Kir channels in kidneys are potential new targets for treating hypertension. "The clue comes from patients with genetic defects in these channels who lose a lot of sodium because it cannot be effectively reabsorbed and thus have low blood pressure," notes Lu. "An inhibitor specifically against these kidney channels will allow this idea to be tested."

Developing a specific inhibitor for one type of Kir channel has been challenging because the target site is very similar among different types of Kir channels. For example, while TPN inhibits Kir type 1 channels in kidney cells, it also inhibits other types of Kir channels in heart cells. After more than a decade, Lu and his colleagues succeeded in bioengineering a TPN that selectively inhibits Kir channels important for salt recycling in kidneys.

By introducing two mutations into TPN, they engineered a variant, called TPNLQ, which stems the flow of potassium ions in renal Kir type 1 channels at low concentrations, and with a 250-fold sensitivity over six other types of Kir channels.

The development of TPNLQ demonstrates that a highly specific inhibitor of potassium channels can be engineered. TPNLQ can now be used as a tool to prove the concept, in animal studies, that reducing salt reabsorption by plugging up renal Kir type 1 potassium channels is a potential new way to treat hypertension.

Yajamana Ramu and Yanping Xu of Penn conducted this study with Dr. Lu. The research was supported by the National Institute of General Medical Sciences and the University of Pennsylvania Research Foundation.

About Hypertension (High Blood Pressure)

High blood pressure is a disorder in which the pressure in the arteries is too high. The medical term for blood pressure that remains high over time is "hypertension".  An estimated 600 million people affected worldwide (Cardiovascular Diseases - Prevention and Control, WHO, 2001-2002) Hypertension, is dangerous because it makes the heart work harder to pump blood to the body and it contributes to hardening of the arteries or atherosclerosis and the development of heart failure.

• Primary hypertension has no specific origin but is strongly associated with lifestyle. It is responsible for 90 to 95 percent of diagnosed hypertension and is treated with stress management, changes in diet, increased physical activity, and medication (if needed).
• Secondary hypertension is responsible for 5 to 10 percent of diagnosed hypertension. It is caused by a preexisting medical condition such as congestive heart failure, kidney failure (renal hypertension), liver failure, or damage to the endocrine (hormone) system (e.g., pheochromocytoma, a rare type of tumor of the adrenal glands that causes production of excessive amounts of adrenal hormones, which cause high blood pressure). Secondary hypertension may be cured if its cause is dealt with.

• Severe headache
• Fatigue or confusion
• Vision problems
• Chest pain
• Difficulty breathing
• Irregular heartbeat
• Blood in the urine