Biomedical Engineering Reference
In-Depth Information
consequence, deactivates the HCN channels, preventing continued departure from
the resting potential. The h-channels possess an inherent negative-feedback prop-
erty. On the contrary, neurotransmitters can influence rhythmic activity in both the
heart and the nervous system by either increasing or decreasing the level of cAMP,
which in turn directly modulates the activation kinetics and maximal current of
HCN channels.
The pacemaker current is not only involved in principal rhythm generation but it
also plays a key role in the regulation of heart rate by the autonomic nervous
system. HCN channels are also implicated in several essential neuronal functions,
which were described elegantly and in great detail by Biel et al. [
16
]. At least seven
physiological roles have been ascribed to the h-current (1) in dendritic integration,
(2) in the control of working memory, (3) in constraining hippocampal LTP (long-
term synaptic plasticity), (4) in motor learning, (5) in synaptic transmission, (6) in
resonance and oscillations, and (7) in the generation of thalamic rhythms.
5 Regulation
One of the most interesting characteristics of the pacemaker current is its regulation
by cyclic nucleotides independently of a phosphorylation process. This mode of
action of cAMP was first demonstrated by inside-out macro-patch f-current studies
in rabbit SAN cells (see Fig.
2b
)[
34
]. It was shown that cAMP directly binds to the
inner face of the channel and facilitates the activation of
I
h
by shifting its voltage
dependence of gating to more positive potentials. Further evidence of this direct
regulation has been demonstrated using cAMP analogues. This study indicates that
the channel's binding site may be structurally similar to the cyclic nucleotide
binding site of olfactory receptor channels [
35
,
36
]. The region implicated in ligand
binding and the functional transfer of cAMP-mediated channel gating is located in
the C-terminus [
37
,
38
]. Wainger et al. [
39
] reported that deletion of the CNBD
shifted the activation curves of HCN channels to more positive voltages by an
amount similar to the maximal shift seen with saturating concentrations of cAMP.
This indicates that cAMP binding enhances gating by removing a basal inhibitory
action operated by the C-terminus. This mechanism had been previously suggested
by Barbuti et al. [
40
]. cAMP shifts the V
1/2
value of human HCN2 and HCN4
channels to more positive voltages. In contrast, HCN1 and HCN3 are only weakly
affected by cAMP [
23
,
37
,
39
]. All pharmacological agents or neurotransmitters,
which are able to induce a change in the intracellular cAMP level modulate the
h-current and consequently influence cellular pacemaking activity. For example,
the adrenergic and cholinergic modulation of heart rate are directly related to the
intracellular cAMP level, with cAMP acting as a major second messenger in
f-channel regulation [
20
]. In the nervous system, serotonergic receptors in mam-
malian and crustacean motoneurons and in mammalian substantia nigra pars
compacta neurons, as well as noradrenergic beta-receptors in neurons of the medial
nucleus of the trapezoid body, and histaminergic H2 receptors in thalamic neurons
