Biomedical Engineering Reference
In-Depth Information
γ
α
1
α
2
+
H
3
N
+
H
3
N
CO
-
I
II
III
IV
δ
Outside
Inside
+
H
3
N
CO
-
CO
-
+
H
3
N
CO
-
Verapamil/
Diltiazem (Ca
v
1)
Dihydropyridines
(Ca
v
1)
ω-Conotoxin
GVIA (Ca
v
2.2)
Gabapentin/
pregabalin
β
+
H
3
N
(A)
CO
-
I
II
III
IV
Site 1 (TTX, STX)
+
+
+
+
+
+
+
+
12345
12345
12345
6
12345
6
Site 1 (μ-conotoxin)
6
Site 2
h
P
Site 3
Site 4
P
Site 5
+
H
3
N
CO
-
P
P
P
P
(B)
FIGURE 13.9
Overview of the binding sites of toxins and drugs acting at (A) Ca
v
and (B) Na
v
channels.
([A] From Catterall, W.A. et al.,
Pharmacol. Rev.
, 57, 385, 2005. With permission from Elsevier; (B) From
Catterall W.A. et al.,
Toxicon
, 49, 124, 2007. With permission from Elsevier.)
dihydropyridine-type compounds, positive modulators of Ca
v
1 have also been identii ed, e.g., the
compound Bay K 8644 (Figure 13.8).
Amino acid residues important for the binding of these compounds have been identii ed through
mutagenesis studies and are located in the S5 and S6 segments of domains III and IV of the
α
1
-subunit (Figure 13.9).
Organic calcium blockers bind with a much higher afi nity to the inactivated conformations of
the Ca
v
s, relative to the closed conformation, thereby trapping the receptors in the inactivated state.
Therefore, inhibition of Ca
v
s by these compounds has been termed “use-dependent:” the rate and
extent of Ca
v
inhibition will increase with channel activation frequency. Use-dependence is gener-
ally considered to be an attractive quality of ion channel inhibitors, since only the highly active
channels—presumably the ones responsible for a given disorder—will be inhibited, while less
frequently activated channels are spared, thereby reducing the risk of side effects.
