Novel Ion Channel Blocker Should Promote Hypertension Research

A team of biophysicists has engineered a specific inhibitor for the Kir1 subgroup of the inward-rectifier K+ (Kir) ion channels that are linked to salt transport in the kidneys and to the regulation of hypertension.

Ion channels are a class of highly specialized membrane proteins that allow ions to flow across the cell membrane in a selective manner. An intricate cell signaling system precisely regulates the opening and closing of ion channels. Ionic currents through ion channels generate electrical voltage across the cell membrane, which underlies the electrical impulses in nerve, muscle, and endocrine cells.

Investigators at the University of Pennsylvania School of Medicine (Philadelphia, USA) have been developing novel protein inhibitors for various types of biologically important ion channels through both passive screening and active protein design-and-engineering. Using thermodynamic mutant cycle analysis, they have investigated both the molecular and the biophysical mechanisms through which protein inhibitors interact with the channels. In addition, they have investigated the mechanisms that determine the molecular specificity between a given protein inhibitor and its targeting channel.

Kir channels play many important biological roles and are emerging as important therapeutic targets. Subtype-specific inhibitors would be useful tools for studying the channels' physiological functions. Unfortunately, available Kir channel inhibitors lack the necessary specificity for their reliable use as pharmacological tools to dissect the various kinds of Kir channel currents

In the current paper, published in the August 5, 2008, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS), investigators reported that they had engineered a mutated version of the honeybee toxin protein tertiapin (TPN). The new molecule, TPNLQ, blocked Kir1 with high (1 nM) affinity and high (>250-fold) selectivity over many commonly studied Kir subtypes.

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,” explained senior author Professor Zhe Lu, professor of physiology at the University of Pennsylvania School of Medicine. "An inhibitor specifically against these kidney channels will allow this idea to be tested.”

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