Lily Jan: Jan Tunes In Potassium Channels
First published May 2003
"I sing the body electric," wrote the poet Walt Whitman a century ago. Indeed, neither poetry nor any human function or form would be possible if electric currents did not pass through our cells.
Helping electricity to flow and thoughts to soar is lowly potassium, the salt of the earth and the seventh most common atom on the planet.
An Enlightenment-era scientist, Sir Humphrey Davy, first used electrolysis -- a battery -- to uncouple potassium from one of its salts, revealing the pure element to be a soft metal. But in a salt or dissolved in water, a potassium atom easily loses an electron and becomes an ion that carries a positive electrical charge.
Within the human body, electrical currents flow in part due to the controlled movement of potassium ions through gated channels embedded in the membranes that envelop cells. "Scientists now have learned that cells in virtually every tissue have potassium channels, often several types," notes Lily Jan, an international expert in the field and a Howard Hughes Medical Institute investigator at UCSF.
Potassium channels allow the heart muscle to contract in a coordinated way, trigger insulin release from beta cells in the pancreas, keep blood pressure under control, allow us to hear by ensuring proper function of hair cells in the ear, and play a role in other, less appreciated physiological phenomena. But for many decades after the discovery of ion flows in the human body, only nerve cells were known to feature such channels.
A new era of molecular genetics was dawning as Lily Jan and her husband Yuh Nung Jan completed their doctoral studies in the early 1970s. The Jans, like their Caltech graduate advisor, Max Delbruck, had long ago switched fields from physics to biology, and they already planned to pursue postdoctoral studies at Caltech with Seymour Benzer, a famed scientist who was revitalizing genetic studies in fruit flies, a model organism used to track genetic traits since the 1920s. The Jans were already interested in the biochemistry of the nervous system, where specific functions for ion channels were first described two decades earlier in a much different model organism.
The flow of potassium ions helps to propagate electrical impulses through the branches, or axons, of nerve cells, and across the synapses between these neurons. This discovery arose from the invention in the 1950s of a crude microelectrode that was applied to the unusually large axon -- visible even to the naked eye -- that propels squid through the ocean.
The time course of the voltages measured in these early squid experiments eventually led to a long-term quest for proteins that would act as selective pores to pump specific ions through the cell membrane and rapidly generate voltage changes within milliseconds, causing "action potentials" to pulse through nerves.
Two decades after these early discoveries, at the conclusion of a summer course probing the frog neuromuscular junction at Long Island's famed Cold Spring Harbor Laboratory, the Jans began mucking around in fruit fly nutrient broth, collecting larvae for genetics studies of behavioral mutants. They decided to work with a "shaker" mutant -- a strain of flies with a tremor.
Homing in on the gene responsible for the shaker mutant was an ambitious goal and painstaking pursuit, but the then-recent invention of "patch clamps," which enabled researchers to take electrical measurements from normal-size nerve cells, and the development of new techniques for manipulating DNA, eventually enabled the Jans and their postdoctoral fellows to become the first to clone a gene for a potassium channel, initially in the fruit fly, and then in the mouse.
Cells also have channels that control the flow of the positively charged ions sodium and calcium, and channels for negatively charged chloride. Similar to the way that electric power companies convert energy from one form to another before delivering it to our homes, cells use chemical energy to pump ions across their membrane and establish ion concentration gradients, and then allow ions to move through specialized channels, making every cell negatively charged compared to its surroundings, and thereby creating an electrical potential that serves as an energy source well suited to performing certain cellular tasks such as the generation of action potentials.
Given the relative simplicity of potassium channels and their presence in all forms of life, including the most evolutionarily primitive, lava-vent-dwelling bacteria, it is easy to speculate that potassium channels arose before other ion channels, and that they model important features found in proteins that evolved later. "We believe that what potassium channels will teach us may be relevant to other membrane proteins," Jan says.
This "voltage-gated" potassium channel first identified and described by the Jans is so named because it serves a rapid feedback function. In a neuron, it opens when sodium ions rush in during an action potential, and as potassium flows out of the cell, the axon membrane returns to its resting electrical potential. When the potassium channel does not function correctly, abnormal signaling results, as in the shaker mutant.
In case one concludes that the study of fruit fly mutants is irrelevant for humans, mutations in the human version of the voltage-gated potassium gene first cloned in the Jan lab have recently been implicated in a nervous disorder called episodic ataxia. "When a medical colleague showed me a movie of a patient with the disorder, I thought her tremor looked amazingly similar to the shaker mutant," Jan says.
In addition, gene mutations in one of the "inwardly rectifying" potassium channels, first cloned by the Jans' group using the frog oocytes, have now been identified by Ying-Hui Fu, and Louis J. Ptacek (both joining the UCSF faculty in the human genetics program) as the cause of certain forms of the Andersen's syndrome associated with arrhythmias, periodic paralysis and dysmorphic features in patients. A number of human diseases including epilepsies, arrhythmias that may cause sudden death, and hypoinsulinemic hypoglycemia of the infancy, have been revealed to result from a defect in other potassium channels.
Still more human disorders caused by potassium channel mutations -- including rare forms of kidney hypertension and congenital deafness -- are coming to light, and even common chronic diseases, such as diabetes and cardiac arrhythmias, are now sometimes treated with drugs that block potassium channels.
"In our lab, people are investigating many different aspects of potassium channels," Jan says. "We are asking how different potassium channels work, how they are regulated by neurotransmitters, by changes in voltage, and by energy levels within the cell. We are wondering whether a cell may also control channel activity by controlling the number of channels on the cell surface. On a molecular level, we want to better understand how the channels allow potassium to pass but exclude smaller ions, such as sodium."
During a heart attack, potassium channels in heart muscle cells open to curtail the toxic influx of calcium ions. While this potassium channel normally remains quietly closed in a healthy heart, a similar channel in the pancreas keeps busy, opening and closing in response to changing sugar levels. Not surprisingly, Jan is curious. "We want to know," she says: "How do differences in the genes of these related channels cause the channel proteins to have different sensitivities to energy levels within the cell?"