Cav1.1
Encyclopedia
Cav1.1 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).
voltage-dependent calcium channel in skeletal muscle
cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility.
Cav1.1 is a voltage-dependent calcium channel
found in the transverse tubule of muscles. In skeletal muscle
it associates with the ryanodine receptor
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 potential
s 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. Recent findings suggest that in skeletal muscle (but not heart muscle), calcium entry through Cav1.1 is not required; Cav1.1 undergoes a conformational change which allosterically activates RyR1.
(HOKPP), the voltage sensors in domains 2 and 4 of Cav1.1 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
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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the CACNA1S gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. It is also known as CACNL1A3 and the dihydropyridine receptor (DHPR).
Function
This gene encodes one of the five subunits of the slowly inactivating L-typeL-type calcium channel
The L-type calcium channel is a type of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties....
voltage-dependent calcium channel in skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility.
Cav1.1 is a voltage-dependent calcium channel
Voltage-dependent calcium channel
Voltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
found in the transverse tubule of muscles. In skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
it associates with the ryanodine receptor
Ryanodine receptor
Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
RyR1 of the sarcoplasmic reticulum via a mechanical linkage. It senses the voltage
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
change caused by the end-plate potential
End-plate potential
End plate potentials are the depolarizations of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance...
from nervous stimulation and propagated by sodium channels as action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s 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
Excitation-contraction coupling
Excitation-contraction coupling is a term coined in 1952 to describe the physiological process of converting an electrical stimulus to a mechanical response . This process is fundamental to muscle physiology, whereby the electrical stimulus is usually an action potential and the mechanical...
, which ultimately causes the muscle to contract. Recent findings suggest that in skeletal muscle (but not heart muscle), calcium entry through Cav1.1 is not required; Cav1.1 undergoes a conformational change which allosterically activates RyR1.
Clinical significance
In hypokalemic periodic paralysisHypokalemic periodic paralysis
Hypokalemic periodic paralysis is a rare channelopathy characterized by muscle weakness or paralysis with a matching fall in potassium levels in the blood...
(HOKPP), the voltage sensors in domains 2 and 4 of Cav1.1 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
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
concentration will cause the muscle to repolarise to the resting potential
Resting potential
The relatively static membrane potential of quiescent cells is called the resting membrane potential , as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential....
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
Hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis is a genetic disorder which occurs in both humans and horses, where it is also known as Impressive Syndrome. It is an inherited autosomal dominant disorder which affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood...
refers to gain-of-function mutations in sodium channels that maintain muscle depolarisation and therefore are aggravated by high potassium ion concentrations.