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For the ordinary feats of life — the beat of a heart, a conscious hand gesture, or the secretion of a critical hormone like insulin — we depend on the complex biological interplay of chemical and electrical signals to relay messages through cellular pathways. How this system works, how connections are made and how ions — the charged atoms that run biology's electrical grid — act on the cell, is not clearly understood.
But key steps in the process came into sharper focus beginning in 1998, when, using x-ray crystallography, HHMI investigator Roderick MacKinnon at The Rockefeller University in New York City, assembled the first detailed picture of an ion channel.
Ion channels are pores in the membranes of cells. Customized to permit only select species of ions — potassium, sodium, calcium, or chloride — to pass through, they are the conduits for all electrical signaling in biology. Consequently, MacKinnon's snapshot of the potassium ion channel was a landmark accomplishment in efforts to understand the mechanics of how ion channels selectively govern the flow of electrical signals through cells. His later work to portray a ligand-gated potassium channel and the voltage-gated ion channels responsible for reloading neurons after they've fired illuminated the details of another essential node of the system whose electrical pulses are responsible for everything from thought to movement. For his accomplishments, MacKinnon was awarded a share of the 2003 Nobel Prize in Chemistry.
For biologists, MacKinnon's work with potassium ion channels provided an elegant model of how that ion passes through its exclusive channel while the smaller sodium ion is excluded. Both kinds of ions travel in the company of water molecules. Entering the channel, they encounter a selectivity filter, which excludes the water molecules. The filter acts in a way, MacKinnon found, that induces the potassium ions to shed their watery escorts, but does not provide sodium ions with the energetic incentive necessary to leave their water molecules behind. Sodium ions are thus prevented from using the larger potassium ion's private portal through the cell's membrane.
To appreciate the importance of potassium channels, consider what potassium ions do: They make the electrical signals that power our hearts and our brains. They aid movement, and they regulate blood pressure by controlling the smooth muscle on the linings of arteries, among other feats. Knowing how these features of the cell work may help in the design of drugs to control seizures in epilepsy, for example, or calm the erratic electrical activity in defective heart muscle.
MacKinnon's subsequent work to model the proteins that make up voltage-gated ion channels, which determine when ions are permitted to pass through a cell's membrane, gave science another highly detailed portrait of an ion conduit. The structures are essential for generating the nerve impulses that underpin things such as movement, sensation, and thought processes.
In muscles and nerves that are electrically active, changes in voltage across the cell membrane help pace the opening of the ion channels. The process, called voltage gating, has been the subject of intense research over many years. MacKinnon's portrait of these proteins was hailed as a signal contribution to the field. His blueprint for the voltage sensor has fueled a new round of research to deduce, precisely, how the voltage gate works. The results will help culminate a 50-year quest for the details of a phenomenon at the heart of essential biological functions.
Photo: Matthew Septimus
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