amino-terminal domain of the mammalian DRKl po- 
tassium channel polypeptide that belongs to a dif- 
ferent subfamily, he detected formation of hetero- 
multimeric channels by this chimera and the Shaker 
potassium channel polypeptide. Thus the hydro- 
phobic core region of the DRKl and Shaker poly- 
peptide are compatible in the subunit interactions, 
even though they only share 40% amino acid iden- 
tity; the failure of the wild-type Shaker and DRKl 
polypeptides to coassemble and form functional 
channels can be attributed to incompatible inter- 
action between their hydrophilic amino-terminal 
domains. 
Structural Elements Involved in Specific 
Potassium Channel Functions 
Voltage-sensitive potassium channels display a 
number of intriguing properties. They contain in- 
trinsic voltage sensors that can detect the electrical 
potential difference across the membrane. In re- 
sponse to appropriate potential changes, these sen- 
sors presumably will cause conformation changes 
that open the channel. The duration that a channel 
stays in the open state is controlled by a process 
called inactivation. Previous studies have revealed 
the presence of a cytoplasmic inactivation gate 
(ball-and-chain) , which is thought to interact with a 
receptor at the cytoplasmic mouth of the channel 
pore after the channel opens, thereby blocking ion 
permeation and causing channel inactivation. While 
a potassium channel is open, potassium ions go 
through the channel pore ~ 1,000 times more 
readily than do other physiologically relevant ions. 
This high level of selectivity has to be achieved in a 
way that is compatible with the large ionic flux: > 1 
million ions can go through a channel in a second. 
Structure-function studies carried out in several lab- 
oratories including that of Dr. Jan have begun to 
associate individual structural elements with spe- 
cific channel functions. 
The hydrophobic core region of a potassium 
channel polypeptide contains seven segments of pre- 
dominantly hydrophobic residues: SI through S6 
and the H5 sequence between S5 and S6. The latter 
has been suggested to form part of the channel pore, 
based on studies by other laboratories. The S4 se- 
quence contains basic residues at every third or 
fourth position and is present in voltage-gated so- 
dium, calcium, and potassium channels. The pro- 
posal that the S4 sequence functions as a voltage 
sensor of the channel is consistent with the observa- 
tion that mutagenesis of either basic or hydrophobic 
residues of the S4 sequence in the Shaker channel 
specifically affects the voltage-dependent proper- 
ties of channel gating, as shown by Drs. Diane Papa- 
zian, Leslie Timpe, and George Lopez. 
The cytoplasmic inactivation gate of the Shaker 
potassium channel has been associated with the 
amino terminus of the Shaker polypeptide; Dr. 
Richard Aldrich (HHMI, Stanford University) has 
shown that, while deletions of residues from the 
amino terminus reduce or eliminate fast inactiva- 
tion, cytoplasmic application of a peptide of the se- 
quence of the Shaker amino terminus restores inac- 
tivation. Similar observations have been made by Dr. 
Tim Baldwin and Dr. Lopez for rat Shall (Kv4.2), a 
mammalian A-type potassium channel gene belong- 
ing to a subfamily different from that of Shaker. 
The receptor for the inactivation gate is likely to 
include five residues in the S4-S5 loop that are 
highly conserved among all four subfamilies of volt- 
age-gated potassium channels, as shown by studies 
by Dr. Isacoflf. Mutations of these residues either in- 
crease or decrease the affinity between the inactiva- 
tion gate and its receptor. These mutations also re- 
duce both the inward and the outward potassium 
ion flux through a single channel pore. Recent stud- 
ies by Dr. Paul Slesinger further reveal that the selec- 
tivity between different permeant ions may be al- 
tered by mutations in the S4-S5 loop. These 
observations strongly suggest that the S4-S5 loop is 
at or near the cytoplasmic opening of the potassium 
channel pore. (The structure-function studies of the 
Shaker potassium channel are supported by the Na- 
tional Institutes of Health.) 
Potassium Channels in the Mammalian Brain 
A surprisingly large number of potassium channel 
genes have been found to be expressed in the mam- 
malian brain; at least 15 such genes have been re- 
ported that give rise to voltage-gated potassium 
channels of fairly similar properties in the Xenopus 
oocyte expression system. Drs. Meei-Ling Tsaur and 
Morgan Sheng have characterized the expression 
patterns of several potassium channel genes in the 
rat brain. Overlapping but clearly distinct patterns 
of gene expression have been found. Moveover the 
expression patterns of some potassium channel 
genes are dynamic in the adult brain; the mRNA lev- 
els of Kvl .2 and Kv4.2 show a transient decrease in 
the excitatory granule cells of the dentate gyrus 
hours after pentylenetetrazole-induced neuronal ac- 
tivities. Thus individual neurons may express differ- 
ent subsets of potassium channel genes and thereby 
acquire their particular characteristics of excitability. 
Recent studies by Drs. Sheng and Baldwin have 
further revealed that certain potassium channel pro- 
teins are differentially localized to either dendrites 
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