Portland, Ore.-Researchers at Oregon Health Sciences University have identified a new family of molecules that play a key role in regulating how we pay attention. Their findings appear in the Sept. 20, 1996 issue of Science and pave the way for the design of drugs to mitigate a wide array of mental and movement disorders including schizophrenia, epilepsy and myotonic dystrophy.
The new family of molecules is a subgroup within a larger superfamily of molecules known as potassium ion channels. Ion channels in general are tiny gateways in the cell membrane that regulate the ebb and flow of electrically charged atoms or ions. The movement of ions such as calcium and potassium causes nerve impulses to travel throughout the body. OHSU scientists led by John P. Adelman, Ph.D., and Jim Maylie, Ph.D., have identified a subgroup of potassium ion channels called SK channels that play a prominent role in the control of cell firing. The SK channels monitor the levels of calcium ions inside the cell. The SK channels then act like rheostats informing the cell of how rapidly it needs to fire by changing the potassium ion balance.
"The SK channels monitor the activity level of the cell and act like tiny rheostats feeding information to the cell regarding its activity level," says Maylie. "The SK channels tell the cell when it is time to slow down or speed up its activity. In skeletal muscle cells the SK channels influence the rapid or slow contraction of a muscle fiber, and in brain cells they influence the rapid or slow release of chemical signals."
Identifying the molecular structure of ion channels and their specific role in cognition is crucial to understanding the molecular basis of the rapid neuronal signaling underlying thinking, learning and memory. When the SK channels fail to function properly certain disease states such as schizophrenia and epilepsy can occur. The SK channels are expressed abundantly in brain regions known to be responsible for cognitive functions such as attention.
"If one interferes with the activity of the SK channels in certain kinds of brain cells, one sees dramatic disconnections in cognitive function in that part of the brain," explains Adelman. "Part of the brain may be cut off from meaningful interactions with other brain regions. Brain cells may fire excessively causing confused and erratic perception and responses characteristic of mental disorders."
Adelman further explains that these molecules provide reasonable intervention sites for therapeutic drugs designed to mitigate disease. For example in patients with myotonic dystrophy, the most common form of inherited dystrophy, it is known that the levels of SK channels are dramatically increased. Blocking those SK channels can alleviate the symptoms, but there are no clinically effective drugs available yet.
"The SK channels can be manipulated to control the disease, but we need to develop more refined pharmacological agents. Knowing the molecular structures of the different members of this family allows us to sort out the subtypes and design drugs that will affect certain areas of the body specifically like diseased muscles or certain defective brain cells.
There is now only one specific molecule known that blocks these channels, a toxin isolated from honey bee venom called apamin. Apamin acts only on a subset of these channels, but now that we know the detailed molecular structure of three of the SK channels scientists can begin to design more effective drugs to manipulate these channels in disease states."
In an accompanying perspective article also appearing in the Sept. 20 issue of Science, Bertil Hille, Ph.D., from the University of Washington writes "This success continues neurobiology's reductionist approach to formerly philosophical questions: What are learning and perception? How does experience rewire cerebral circuits? In this heady paradigm, all molecules and their regulation must be known. Because ion channels make and pattern the electrical messages that are the currency of rapid neuronal signaling, they are high on the list. Almost yearly, members of new families of channels are cloned and catapulted to prominence."