Ca
v1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a
protein which in humans is encoded by the ''CACNA1S''
gene.
It is also known as CACNL1A3 and the
dihydropyridine receptor (DHPR, so named due to the blocking action DHP has on it).
Function
This gene encodes one of the five subunits of the slowly inactivating
L-type voltage-dependent calcium channel in
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
cells. Mutations in this gene have been associated with
hypokalemic periodic paralysis,
thyrotoxic periodic paralysis
Thyrotoxic periodic paralysis (TPP) is a condition featuring attacks of muscle weakness in the presence of hyperthyroidism (overactivity of the thyroid gland). Hypokalemia (a decreased potassium level in the blood) is usually present during atta ...
and
malignant hyperthermia susceptibility.
Ca
v1.1 is a
voltage-dependent calcium channel found in the
transverse tubule
T-tubules (transverse tubules) are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells. With membranes that contain large concentrations of ion channels, transporters, and pumps, T-tubules permit ...
of muscles. In
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
it associates with the
ryanodine receptor
Ryanodine receptors (RyR for short) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons.
There are three major isoforms of the ryanodine receptor, which are found in different tissu ...
RyR1 of the
sarcoplasmic reticulum via a mechanical linkage. It senses the
voltage change caused by the
end-plate potential from nervous stimulation and propagated by sodium channels as
action potentials to the T-tubules. It was previously thought that when the muscle depolarises, the calcium channel opens, allowing calcium in and activating RyR1, which mediates much greater calcium release from the sarcoplasmic reticulum. This is the first part of the process of
excitation-contraction coupling, which ultimately causes the muscle to contract. Calcium entry through Cav1.1 is not required in skeletal muscle, as it is in cardiac muscle; Cav1.1 undergoes a conformational change which allosterically activates RyR1.
Clinical significance
In
hypokalemic periodic paralysis (HOKPP), the voltage sensors in domains 2 and 4 of Ca
v1.1 are mutated (loss-of-function), reducing the availability of the channel to sense depolarisation, and therefore it cannot activate the ryanodine receptor as efficiently. As a result, the muscle cannot contract very well and the patient is paralysed. The condition is hypokalemic because a low extracellular potassium
ion concentration will cause the muscle to repolarise to the
resting potential A relatively static membrane potential which is usually referred to as the ground value for trans-membrane voltage.
The relatively static membrane potential of quiescent cells is called the resting membrane potential (or resting voltage), as oppo ...
more quickly, so any calcium conductance that does occur cannot be sustained. It becomes more difficult to reach the threshold at which the muscle can contract, and even if this is reached then the muscle is more prone to relaxing. Because of this, the severity would be reduced if potassium ion concentrations are maintained. In contrast,
hyperkalemic periodic paralysis refers to gain-of-function mutations in sodium channels that maintain muscle depolarisation and therefore are aggravated by ''high'' potassium ion concentrations.
The European
Malignant Hyperthermia Group accepts two mutations in CACNA1S as diagnostic for malignant hyperthermia.
Blockers
Ca
v1.1 is
blocked by
dihydropyridine.
See also
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Calcium channel
A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels.
Comparison tables
The following tables e ...
References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on Malignant Hyperthermia Susceptibility*
{{Ion channels, g1
Ion channels