Biomedical Engineering Reference
In-Depth Information
2.3 Sequential (Ontogenetic) Appearance of Membrane Currents
Recent progress in genetic engineering has renewed the interest in the early
development of the mouse heart. The order by which membrane currents appear in the
embryonic heart has thus far been restricted to studies in mice embryos [12] and in
cell cultures derived from mouse embryonic stem cells (for review see [24]). The
slow inward calcium current (
I
Ca-L
) has been demonstrated at 9.5 days post coitum
(dpc) [30] and increases steadily until birth at 19 dpc, [12, 30], whereas the fast
inward sodium current (
I
Na
) becomes prominent at later stage [12]. With respect to the
repolarizing currents the transient outward current (
I
to1
) develops first [12, 24, 67]
with higher atrial than ventricular density [12]. Other outward potassium currents
develop later with different regional densities [12]. Thus, cells at 11-13 dpc depend
on
I
Ca-L
for the upstroke and on
I
to
1 for repolarization of their action potentials in line
with the observation that these currents develop also first in cells derived from mouse
embryonic stem cells [24, 67]. Figure 2 (from [67]) shows a putative scheme with
sequential development of membrane currents in the embryonic murine ventricle. The
horizontal arrow at the top of Fig. 2 shows supposed development, whereas the arrow
at the bottom of Fig. 2 indicates the order by which membrane currents might
(re)appear when the view is taken that under certain pathological conditions a foetal
gene program is recapitulated. It goes without saying that the latter is highly
speculative. The pacemaker current
I
f
plays a prominent role in pacemaking in the
adult sinus node, also in man. Figure 2 shows that this current disappears around birth
from the embryonic murine ventricle. Reintroducing it in ventricle therefore
introduces a current that is normally absent in ventricle.
2.4 Role of Pacemaker Currents with Focus on
I
f
The embryonic mouse heart starts to beat at 8.5 dpc. The full gestation period takes 21
days. Figure 3a (taken from [66]) shows that ventricular myocytes from hearts at 9.5
dpc exhibit spontaneous activity and Fig. 3c shows the presence of inward current
activating upon hyperpolarization, which is a feature of the pacemaker current
I
f
. At
18 dpc, that is 3 days before birth, the action potential configuration has changed
substantially, spontaneous activity has slowed down and has lost regularity (Fig. 3b).
The
I
f
current has disappeared almost completely shortly before birth (Fig. 3d). The
fact that these ventricular myocytes display automaticity at early development does
not exclude that the sinus node drives the embryonic heart from the very onset of
electrical activity as in the chicken heart [59], but experimental proof for this is
lacking. The right panel of Fig. 3 shows that the principal ion channel subunit at 9.5
dpc is based on expression of HCN4, which is a member of the hyperpolarization-
activated cyclic nucleotide-gated (HCN) family of genes [4] and which is underlying
the
I
f
current of the adult sinus node. During the second half of embryonic
development the expression of HCN4 mRNA disappears almost completely (Fig. 3,
right panel). HCN2, which is virtually the only expressed HCN gene in adult working
atrial and ventricular myocytes, displays low expression during the full period of
embryonic development. The role of the HCN2 based
I
f
current in adult atrium and
ventricle is unclear, given the negative potential range where this current activates
[45]. It thus seems as if immature ventricular myocytes are more or less sinus node
