The gene, known as K2P6.1 or TWIK-2, is one of a family of potassium channel genes first discovered in the 1990s. In general, ion channels are tiny pores that, when opened, allow charged ions such as sodium, potassium or calcium to flow in and out of cells. Potassium channels allow only the flow of potassium while excluding all other ions. The TWIK-2 channel and other members of this family require two protein subunits to associate to form a fully functional channel, while other potassium channels require four protein subunits.
“The interesting thing about this gene is that it does not seem to be expressed (have activity) in the brain or neurons,” said Dr. Robert Bryan, professor of anesthesiology at BCM and a corresponding author of the report. “All studies show that it is expressed in the vasculature. We decided it likely had some important role in regulating the diameter of blood vessels.” Blood vessel diameter affects the flow of blood and, ultimately, blood pressure.
To understand this better, they developed a mouse that lacked this particular gene.
“All of these mice were hypertensive,” said Dr. Eric Lloyd, instructor in the department of anesthesiology at BCM. “And they were hypertensive at a very young age. This is the first time that loss of a potassium channel caused this severity of hypertension in a young mouse without an external influence.”
Further studies indicate that loss of this gene increases the activity of rho kinase, an enzyme that makes vascular smooth muscle more sensitive to calcium, the chemical that triggers vessel contraction. When they gave the animals a drug that blocked rho kinase activity, the contraction of their smooth muscle became more normal.
Inactivating TWIK-2 changes the electrical charge of the cell membrane in smooth muscle, which can affect flow of ions in or out of the cell.
“If we could find something to activate TWIK-2, the idea would be that we could control hypertension (high blood pressure),” said Lloyd.
Others who took part in this research include Randy F. Crossland, Sharon C. Phillips, Dr. Sean P. Marrelli, Dr. Anilkumar K. Reddy Dr. George E. Taffet and Dr. Craig J. Hartley, all of BCM.
Funding for this work came from the National Institutes of Health.