Bacterial Ion Channel, a Platform for Screening Ion Channel Agonists and Antagonists
Inventors: David Clapham, Dejian Ren
Invention Types: Research Tool
Research Areas: Cardiovascular/Cardiology, Gastrointestinal/Nutrition, Neurology/Neuroscience
Keywords: Drug Screening, Ion ChannelsFor More Information Contact: Herrera Gutierrez, Aida
The pore-forming subunits of canonical voltage-gated sodium and calcium channels are encoded by four repeated domains of 6 transmembrane spanning (6TM) segments. Investigators at Children's Hospital expressed and characterized a bacterial ion channel from Bacillus halodurans that is encoded by one 6TM segment. The pore region of the novel channel is homologous to that of voltage-gated calcium channels. In addition, the expressed channel is activated by voltage, and is blocked by calcium channel blockers. Despite this resemblance to Cav channels, the novel channel is selective for sodium. This novel protein represents the first bacterial voltage-sensitive ion-selective channel, as well as the first functionally expressed Cav or Nav composed of only 6 transmembrane domains.
We anticipate this bacterial protein could be used as a platform technology for the high level expression of mammalian ion channel pore domains in mammalian or bacterial cells. The idea is to insert the pore region of known mammalian ion channels into this minimal bacterial structure. The hybrid proteins could then be screened for activation or inhibition by various compounds. The advantages of this system would include:
-A minimal length structure that is highly expressed in mammalian cells.
-The expressed bacterial ion channel is functionally active in a heterologous cell system.
The advantages of this system would include: A minimal length structure that is highly expressed in mammalian cells and the expressed bacterial ion channel is functionally active in a heterologous cell system. Voltage-gated potassium (Kv), sodium (Nav), and calcium (Cav) channels support specialized higher order cell functions such as excitability, contraction, secretion, and synaptic transmission. Hundreds of Kv, Nav, Cav channel proteins provide the tremendous functional diversity required for the complex behaviors of eukaryotic vertebrate and invertebrate cell-types. Certain diseases such as the Long QT syndrome, which claims the lives of about 4,000 American children and young adults yearly, are caused by an ion channel defect. Ion channel blockers have been used to treat a number of cardiovascular diseases such as high blood pressure, angina, and atrial fibrillation. Atrial Fibrillation alone affects over 2.5 million people in the US, with an estimated 160,000 new cases diagnosed each year, and an estimated annual cost of $1 billion. In addition, it is anticipated that ion channel modulators will be useful for treating many other diseases including central nervous system disorders, and gastrointestinal diseases.
Key Publications: Ren D, Navarro B, Xu H, et al. A prokaryotic voltage-gated sodium channel. Science. 2001 Dec 14;294(5550):2372-2375.