Biomedical Engineering Reference
In-Depth Information
that can only be monitored with high gain amplifiers. The patch
clamp technique is the state-of-the-art technology for the study of
ion channels,
3
but patch clamping is a laborious process requiring
skilled and highly trained scientists. Owing to its ultra-low
throughput, conventional patch clamp is frequently applied only in
the later stages of drug discovery and development. To be able to
search for new drug candidates at an earlier stage of drug devel-
opment, high throughput screening assays are required. In recent
years, new methods have been developed, which are a trade-off
between high throughput and high information content. These so-
called automated patch clamp systems
4-6
provide a platform, which
allows for the investigation of ion channels from a functional per-
spective, i.e., the electrical characteristics of ion channels and their
modulation by drugs can be monitored in great detail. Automated
patch clamp, however, relies on currents in the picoampere regime,
which are generated by a single ion channel, and data workup of
these single events is rather tedious.
Hence, integral methods such as impedance spectroscopy, cy-
clovoltammetry or chronoamperometry are in some cases advanta-
geous. For example, electrogenic transporter proteins exhibit
transport rates of only 10-1000 s
-1
and, thus, the electrical activity
of a single protein cannot be detected. To obtain a detectable elec-
trical current in the range of picoamperes, at least 10
4
transporters
have to work in concert. Some of the most profitable drugs are in-
hibitors for transport proteins, and many transporters are possible
targets for new drug developments. For example, ouabain and di-
goxin act on the cardiac muscle cell Na
+
/K
+
-ATPase in patients
with congestive heart failure, while fluoxetine and imipramine are
inhibitors of the sodium coupled serotonin transporter that are used
as antidepressants. The gastric proton pump of the stomach muco-
sa is a drug target to treat ulcers and gastric reflux, which is medi-
cated with omeprazole, lanosprazole, pantoprazole, and paripra-
zole. It is obvious that new approaches are necessary to develop
bioanalytical devices and drug screening techniques for the phar-
maceutical industry, targeting transport proteins as well as ion
channels in an integral manner.
A number of approaches are based on lipid membranes that
are attached to a conducting solid substrate such as gold, platinum
or indium tin oxide. To establish solid supported membranes, ei-
ther two separate monolayers can be deposited on the material by
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