Biomedical Engineering Reference
In-Depth Information
also shown to block the neuronal
I
h
current, although with less affinity than in
cardiac cells [
94
,
95
]. Precise mechanisms and molecular determinants of the effects
of ZD 7288 have been the subject of continued efforts. In 2001, Shin and
collaborators [
96
] characterized
I
f
blockade mechanisms by specific analysis of
the effects of ZD 7288 on HCN1 expressed in HEK293 cells. They found that the
blocking effects of ZD 7288 required channel opening and that the drug was trapped
by closing of the channel. Interestingly, the ZD 7288 binding site has been located in
the pore lining of the channel. A recent study by Cheng et al. mapped the binding site
of ZD 7288 on HCN2 expressed in Xenopus oocytes [
65
]. Using site-directed
mutagenesis, these authors reported that two amino acids located in the 6th trans-
membrane domain of the protein (Ala425 and Ile432) were determinant for the
effect of the compound.
7 Conclusions and Future Directions
The hyperpolarization-activated cation current is clearly an important target for the
treatment of stable angina in the heart. Modulation of
I
h
may also be a promising
approach for the treatment of disease processes in the central and peripheral
nervous systems. Several results suggest that HCN channels also play a prominent
role in neuropathic pain (for recent review, see [
97
]). In this case
,I
h
blockers could
be beneficial for analgesic therapy. Furthermore, the use of
I
h
blockers has also been
implicated in epilepsy therapy [
98
]. However, given the complexity of the cellular
mechanisms leading to these diseases, a clear notion for a rational design of
antiepileptic
I
h
channel modulators has not yet emerged. Finally, HCN channels
may contribute to the clinical actions of general anesthetics. Native neuronal
I
h
as
well as heterologously expressed HCN channels are inhibited by clinically relevant
concentrations of anesthetics [
99
-
102
]
.
In principle, existing blockers could be
plausible molecular candidates. Nevertheless, these drugs inhibit all HCN isoforms
with no apparent subtype selectivity and would also exert bradycardic effects. Ideal
I
h
neuronal blockers should not interfere with the function of sinoatrial HCN4
channels.
HCN isoforms could serve as new genetic targets in the modulation of cellular
rhythmicity. For example, it was shown that HCN4 mutations underlie certain
congenital cardiac arrhythmias such as the inherited form of the sick sinus syn-
drome [
103
]. Furthermore, it is essential to amplify the range of available thera-
peutic agents specifically targeting cardiac pacemaker channels, for instance. In this
way, high affinity, subtype-specific HCN channel blockers must be developed.
Moreover, one of the most important challenges in the coming years is the devel-
opment of biological pacemakers, which may replace electronic devices. Indeed,
pacemaker cells derived from stem cells and/or the stable in situ transfection of
HCN channels represent a promising novel approach for the development of such
pacemakers.
