Biomedical Engineering Reference
In-Depth Information
Abbreviations
DHPs
Dihydropyridines
HVA
High-voltage-activated
L
-type Ca
2
þ
ion channels
LCC
LSSVM
Least squares support vector machine
QSAR
Quantitative SAR structure-activity relationships
QTMS
Quantum topological molecular similarity
SAR
Structure-activity relationships
VDCCs
Voltage-dependent calcium channels
1
Introduction
1.1 Calcium Ion Channels
Calcium is essential in all living organisms and a ubiquitous second messenger.
The influx of calcium ions into cells is involved in numerous intracellular events.
Calcium entry into the cytosol is mediated by multiple types of calcium channels
and ligand-dependent calcium channel, each with a distinct physiological role [
1
].
Ca
2
þ
channels are hetero-oligomeric protein complexes consisting of a pore-
forming a1-subunit, one out of at least four b-subunits (b1-b4), an a2/d-subunit,
and in skeletal muscle of an additional g-subunit [
2
,
3
]. The auxiliary channel
subunits, in particular the b-subunits, modulate voltage dependence, expression
density and kinetics of the channels. Calcium ion channels were first identified by
Fatt and Katz in crustacean muscle when they left the Na
+
out of their bathing
medium and found that the muscle still generated action potential [
4
]. Fatt and
Ginsborg investigated in detail the significance of this observation [
5
]. In continua-
tion, Hagiwara and Byerly [
6
] studied in depth the calcium conductance in various
invertebrate tissues.
Calcium channels have major roles in both normal functioning and in patho-
logies affecting neuronal, neurosecretory and muscle cells [
7
]. It has become
apparent that in several tissues, including certain cardiac muscle cells and subse-
quently, neurons and other excitable cells, there are two types of calcium ions
channels. One is activated by small depolarization and shows rapid voltage-
dependent inactivation; this is termed “low-voltage-activated,” or “T” (for transient).
The second is activated by large depolarization and is termed “high-voltage-
activated” (HVA). At least five different types of voltage-dependent Ca
2
þ
channel
(VDCCs) exist in electrically excitable mammalian cells. Biophysical and pharma-
cological studies have identified four subtypes of high-voltage-activated (HVA)
calcium channels that are encoded by a family of seven different a1 subunit proteins
(Cav) as L, N, P, Q, R or T-types.
L
-type (Cav1.1-Cav1.4), N-type (Cav2.2),
P/Q-type (Cav2.1), and R-type (Cav2.3) as well as
low-voltage-activated
