Biomedical Engineering Reference
In-Depth Information
may function in synaptic plasticity and the activation of sperm [
5
]. A notable
characteristic feature of pacemaker channels is their modulation by cyclic
nucleotides, i.e., cAMP and cGMP, independently of a phosphorylation process.
In the 1990s, several cDNAs encoding pacemaker channels were isolated by
molecular cloning [
6
-
9
]. On the basis of amino acid sequencing, four mammalian
genes were revealed to code for members of the voltage-gated K (Kv) channel
superfamily, and cyclic nucleotide-gated channels (see [
10
] for review). With
regard to their dual properties, the channels were termed hyperpolarization-
activated cyclic nucleotide-gated cation (HCN) channels. The four isoforms have
diverse properties and variable expression patterns and can form functional
heteromultimers with particular biophysical and regulatory properties.
Because of their fundamental role in cellular pacemaking, HCN channels are
considered as relevant pharmacological targets, in particular with respect to the control
of heart beat. A number of organic compounds have been described that block the
pacemaker current in a relatively specific manner. Drug interactions and potential
applications of their therapeutic use on the pacemaker current will be discussed below.
2 Molecular Structure
As described above, HCN channels belong to the family of cyclic-nucleotide gated
channels and may be structurally related to voltage-sensitive potassium channels
[
11
,
12
]. Four main isoforms (see Fig.
1a
), named HCN1 to HCN4, have been
identified so far. The tissue distribution of HCN1, HCN2, HCN3 and HCN4 is
heterogeneous, and specific expression of the different isoforms can be summarized
briefly as follows: HCN1 is expressed in different regions of the central nervous
system (olfactory bulb, cerebral cortex, hippocampus, superior colliculus, and
cerebellum) and peripheral nervous system (dorsal root ganglion) [
14
]. HCN2 is
present in most brain regions, with highest expression levels in the olfactory bulb,
hippocampus, thalamus, and brain stem. HCN3 is widely expressed in the brain, but
at low levels. HCN4 transcripts are selectively expressed in the thalamus and
olfactory bulb. Besides expression in the peripheral and central nervous systems,
HCN1, HCN2, and HCN4 are expressed in the heart with specific differences
according to cardiac regions and species [
15
,
16
].
All isoforms are composed of six transmembrane segments (see Fig.
1a, b
)
organized in a similar manner to other voltage-sensitive ion channels, i.e., voltage
sensing located in the fourth segment and pore region between the fifth and the sixth
segments. Voltage sensing is attributed to repetitive, positively charged amino acids
(Lys and Arg) in the fourth segment, with activation or deactivation of the channel
taking place according to changes in the transmembrane electrical field. While
HCN channels are permeable to sodium and potassium, the pore region is
characterized by a GYG sequence, which is generally considered to be a specific
requirement for K channel selectivity. No clear explanation for this apparent
contradiction has yet been provided. In addition to this classical transmembrane
