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might compensatorily be upregulated (
29, 31
). Voltage-gated K
+
channels were suggested to trigger acute effects, while expression
changes of voltage-gated Ca
2+
channels occur during delayed vasos-
pasm (
20
). However, the role of expression changes of voltage-
gated Ca
2+
channels is yet not understood.
3.8. SAH-Knockout
Models
Besides these methods, usage of an SAH-knockout model is a pos-
sibility for an evaluation of the physiological and pathophysiologi-
cal role of a particular ion channel. Such an analysis has recently
been performed for the role of adenosine A receptors in early isch-
emic vascular injury after SAH (
49
). Comparison of wild type and
gene-manipulated animals might reveal striking differences and
subsequently might give insights in ion channel function.
Meanwhile, Ca
2+
channel-defi cient mice have been established for
nearly all pore-forming subunits, but to our knowledge never used
in SAH models. In part, results from experiments of ion channel
defi cient animals are hard to interpret. One should consider that
loss of a particular ion channel usually leads to partial compensa-
tion by others. As an example, such a compensatory upregulation
R-type and N-type Ca
2+
channel occurs at the neuromuscular end-
plate of Ca
v
1.2-defi cient mice (
36, 37
).
3.9. Analysis of the
Role of Ion Channel
Interaction Partners
Ion channels are embedded in the functional or pathophysiologi-
cally disturbed network of the cell. Therefore, assessment has not
only to focus on particular ion channels but also on their role in this
network. The evaluation is important for understanding the mecha-
nisms following SAH-induced cerebral vasospasm. Here, interac-
tion partner plays an important role. Several regulatory proteins
underlie molecular changes following SAH. As one example, pro-
tein kinase C (PKC) is mainly involved in the pathogenesis of cere-
bral vasospasms following SAH with an activation of the
PKC-dependent contractile system (
50, 51
). Hemoglobin changes
levels of PKC expression and different isoforms of the protein kinase
are translocated from the cytosol to the plasma membrane after
SAH (PKC-
δ
on day 4 and PKC-
α
on day 7) (
52
). Therefore, it was
considered that PKC-
is involved in initiation of SAH-induced
vasospasm, whereas PKC-
δ
plays a role in its maintenance (
53, 54
).
As a classical target of modulation, PKC phosphorylates the Ca
v
1.2
subunit of L-type calcium channels and leads to dual modulation
with inhibitory and stimulatory effects in vascular smooth muscle
cells. Further, PKC is involved in the Ca
2+
-dependent stimulation of
Ca
v
2.3. Interestingly, calmodulin, another regulatory protein of
voltage-gated Ca
2+
channels, was considered to decrease within 48 h
after SAH in a canine model (
55
). One might speculate, if imbal-
ance of calmodulin-mediated inactivation and PKC-mediated Ca
2+
-
dependent stimulation of R-type calcium channels might lead to
self-perpetuating Ca
2+
infl ux during vasospasm. Therefore, further
studies should also address interaction partners of voltage-gated cal-
cium channels and elucidate their role within the cellular network.
α
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