Molecular Studies of Voltage-Sensitive 
Potassium Channels 
Lily Y.Jan, Ph.D. — Investigator 
Dr. Jan is also Professor of Physiology and Biochemistry at the University of California, San Francisco. 
During her graduate study at the California Institute of Technology with Jean Paul Revel and Max Del- 
briick, Dr. Jan localized the visual pigment rhodopsin at the ultrastructural level. Her Ph.D. degree was 
in physics and biophysics, mainly because she studied high-energy theoretical physics before becoming a 
biology student. After graduate school she stayed at CalTech to do postdoctoral research with Seymour 
Benzer and began to collaborate with her husband, Yuh Nung Jan. Their first collaboration resulted in 
the identification of the Shaker locus as a potential structural gene for a potassium channel. Before ac- 
cepting faculty appointments at UCSP, the Jans worked in Stephen Kuffler's laboratory at Harvard Medical 
School. 
VOLTAGE-sensitive potassium channels proba- 
bly constitute the most diverse and wide- 
spread class of ion channels. More than 30 differ- 
ent types of potassium channels have been 
characterized. They dilfer in their voltage sensi- 
tivity, their kinetic properties, and their sensitiv- 
ity to second messengers within the cell. Potas- 
sium channels have been found in almost every 
eukaryotic cell type examined, in both the ani- 
mal and the plant kingdoms. They are important 
for a wide range of physiological functions, in- 
cluding insulin release due to raised glucose lev- 
els, proliferation of lymphocytes induced by mi- 
togens, and the movements of leaflets in plants or 
the opening and closing of leaf stomatal pores. In 
the mammalian nervous system, potassium chan- 
nels control excitability and the strength of sig- 
naling between nerve cells. Indeed, some of the 
potassium channels have been implicated as 
playing a role in learning and memory. 
In order to study how the diversity of potas- 
sium channels arises and how they serve the wide 
variety of cellular functions, one needs to study 
these channels biochemically as well as biophysi- 
cally. However, they are difficult to purify be- 
cause they are rather heterogeneous and inacces- 
sible. For this reason we have taken advantage of 
the well-developed genetic technologies applica- 
ble to the fruit fly Drosophila melanogaster. In 
this organism, if a gene (say, coding for a potas- 
sium channel) can be identified by the abnormali- 
ties caused by its mutations, one can clone it for 
molecular studies of the gene product. 
More than a decade ago, Yuh Nung Jan (HHMI, 
University of California, San Francisco), Mike 
Dennis, and I found that mutations at the Shaker 
locus cause prolonged transmitter release from 
the motor nerve terminal, probably because of a 
defect in potassium channel function. Subse- 
quent studies by Larry Salkoff, Mark Tanouye, Al- 
berto Ferrus, C. F. Wu, and Leslie Timpe provided 
strong evidence suggesting that the Shaker locus 
codes for a component of a rapidly inactivating 
potassium channel, the A channel. The locus was 
subsequently cloned by Diane Papazian, Tom 
Schwarz, and Bruce Tempel in our laboratory. It 
codes for proteins that contain multiple stretches 
of hydrophobic amino acids that can potentially 
span the cell membrane. 
These Shaker proteins appear to be integral 
membrane proteins, as indicated by their se- 
quence and by subsequent immunoblot (West- 
ern) studies. They show homology to the se- 
quence of vertebrate sodium channels, although 
they are much smaller in size. They correspond 
roughly to one of the four internally homologous 
domains of the sodium channel. Finally, Dr. 
Timpe demonstrated that RNA encoding for four 
of the Shaker proteins of known deduced se- 
quence, when injected into frog oocytes, causes 
the functional expression of potassium channels 
that in several ways resemble the A channel in the 
fruit fly. Taken together, these studies showed 
that the Shaker locus is a potassium channel 
gene. 
Starting with the Shaker gene in the fruit fly. 
Dr. Tempel isolated a gene in the mouse that 
codes for a potassium channel in the mouse 
brain. This protein is 65 percent identical in its 
sequence to the Drosophila potassium channel 
protein. In frog oocytes, the gene produces potas- 
sium channels that do not inactivate rapidly. Anal- 
ysis of the distribution of amino acid residues that 
appear to be essential and have been totally con- 
served over 600 million years has provided some 
clues to the channel's structure. By now more 
than 10 different mammalian potassium channel 
genes have been characterized by a number of 
laboratories. One of these (the rat Shall gene), 
cloned and characterized in our laboratory by 
Tim Baldwin, Meei-Ling Tsaur, and George Lo- 
pez, produces a rapidly inactivating potassium 
channel in frog oocytes and is expressed in the 
heart as well as the brain. The high degree of con- 
servation between these mammalian and the fruit 
fly potassium channels reiterates the point that 
217 
