Biomedical Engineering Reference
In-Depth Information
Ca
v
s are several 1000-fold selective for Ca
2+
ions over Na
+
and K
+
and this amazing selectivity is
created by a ring of four negatively charged glutamic acid residues projecting into the ion channel
pore, one such residue being contributed by each of the four pore loops. Ten different
α
1
-subunit
types have been cloned and based on their amino acid homology, these have been divided into
three distinct families (Ca
v
1, Ca
v
2, and Ca
v
3) that display 30%-50% amino acid identity with
each other. Within each family there are three to four members (Ca
v
1.1- Ca
v
1.4, Ca
v
2.1-Ca
v
2.3,
and Cav3.1-Cav3.3) that each show a much higher degree of sequence identity (~80%) with
each other. The Ca
v
1.1-subunit is only expressed in skeletal and cardiac muscle, and the Cav1.4-
subunit is exclusively expressed in retina. The other
α
1
-subunits are widely expressed in many
tissues, in particular the peripheral and central nervous system (CNS) as well as many types of
endocrine cells.
When expressed alone, the
α
1
-subunit can form a functional ion channel. But native Ca
v
s are mul-
tisubunit complexes in which the
-subunit
(Figure 13.7B). The role of these subunits is to promote incorporation of Ca
v
into the cell membrane
and to modulate the functional properties of Ca
v
s.
α
1
-subunit interacts with a
β
-, an
α
2
δ
- and sometimes a
γ
13.3.2 P
HYSIOLOGICAL
R
OLES
OF
V
OLTAGE
-G
ATED
C
ALCIUM
C
HANNELS
Ca
2+
is an important second messenger molecule in eukaryotic cells where it initiates muscle con-
traction, neurotransmitter release, and activates many types of protein kinases. Many homeostatic
mechanisms operate to keep intracellular [Ca
2+
] < 100 nM under resting conditions. Outside the cell,
[Ca
2+
] is 1-2 mM, creating a 10,000-fold concentration gradient. The Ca
2+
-equilibrium potential is
> +100 mV so Ca
2+
always l ows into a cell, when Ca
v
s are activated by depolarization. While the
primary function of voltage-gated Na
+
and K
+
channels is to produce depolarization/repolarization
of the cell membrane, voltage-gated Ca
2+
channels should be thought of as “gatekeepers” of calcium
entry into excitable cells.
In muscle tissue, the binding of Ca
2+
to the protein troponin C allows myosin-mediated sliding
of actin-i laments, leading to shortening of muscle i bers. In skeletal muscle, the calcium necessary
for this process actually comes from the sarcoplasmic reticulum and is released from this into the
cytoplasm via ryanodine receptors. In this particular context, the Ca
v
functions as a voltage-sensor
for the process—a direct interaction between the Ca
v
1.1
α
1
-subunit and the ryanodine receptors then
activates the Ca
2+
release.
Ca
v
s are also very important in cardiac and smooth muscles, where direct Ca
2+
-inl ux through the
Ca
v
itself provides the Ca
2+
necessary for muscular contraction. In cardiac muscle, Ca
v
1.2 or Ca
v
1.3
is responsible for the plateau-phase of the cardiac action potential, which is important for cardiac
muscle contraction and for regulation of the heart rate, so dihydropyridines are used for treatment of
hypertension and cardiac arrhythmia. Ca
v
3.1- and Ca
v
3.2-subunits are found in the sino-atrial nodes
where they play important roles for cardiac pacemaking.
The release of neurotransmitters from synaptic nerve terminals is triggered by inl ux of Ca
2+
ions
via Ca
v
2.1- (P/Q-type) or Ca
v
2.2- (N-type) subunits, which are expressed in all nerve terminals. When
neuronal action potentials travel down the axon and reach the nerve terminal, they provide the depo-
larization necessary for activation of Ca
v
s leading to Ca
2+
-inl ux. The Ca
v
2.1 and Ca
v
2.2 subunits
bind directly to proteins of the protein-machinery involved in membrane fusion of neurotransmitter-
containing vesicles.
A similar role of Ca
v
s is found in various endocrine cells such as the pancreatic
-cells in which
ATP-mediated closing of K
ATP
-channels leads to cellular depolarization, activation of Ca
v
1.3 chan-
nels, and release of insulin-containing vesicles (Figure 13.5).
β
13.3.3 P
HARMACOLOGY
OF
V
OLTAGE
-G
ATED
C
ALCIUM
C
HANNELS
There are two types of inhibition of Ca
v
function, namely, blockade of the ion channel pore and
allosteric modulation of ion channel function. An example of pore blockade is cadmium (Cd
2+
),
