Calcium channel, voltage-dependent, L type, alpha 1C subunit (also known as Ca_v1.2) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

that in humans is encoded by the ''CACNA1C''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. Ca_v1.2 is a subunit of L-type

voltage-dependent calcium channel Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeab ...

Structure and function

This gene encodes an alpha-1 subunit of a voltage-dependent

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...

channel. Calcium channels mediate the influx of calcium

ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...

s (Ca²⁺) into the cell upon membrane polarization (see

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charge ...

and

calcium in biology Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of ...

). The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta and beta subunits in a 1:1:1 ratio. The S3-S4 linkers of Cav1.2 determine the gating phenotype and modulated gating kinetics of the channel. Cav1.2 is widely expressed in the

smooth muscle Smooth muscle is an involuntary non- striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit ...

pancreatic The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endoc ...

cells,

fibroblast A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of ...

s, and

neuron A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous ...

s. However, it is particularly important and well known for its expression in the heart where it mediates L-type currents, which causes calcium-induced calcium release from the ER Stores via

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 ...

s. It depolarizes at -30 mV and helps define the shape of the action potential in

cardiac The heart is a muscular organ found in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon di ...

and smooth muscle. The protein encoded by this gene binds to and is inhibited by dihydropyridine. In the arteries of the brain, high levels of calcium in mitochondria elevates activity of nuclear factor kappa B

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

and transcription of CACNA1c and functional Cav1.2 expression increases. Cav1.2 also regulates levels of

osteoprotegerin Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by the ...

. Ca_V1.2 is inhibited by the action of STIM1.

Regulation

The activity of CaV1.2 channels is tightly regulated by the Ca²⁺ signals they produce. An increase in intracellular Ca²⁺ concentration implicated in Cav1.2 facilitation, a form of positive feedback called Ca²⁺-dependent facilitation, that amplifies Ca²⁺ influx. In addition, increasing influx intracellular Ca²⁺ concentration has implicated to exert the opposite effect Ca2+ dependent inactivation. These activation and inactivation mechanisms both involve Ca²⁺ binding to calmodulin (CaM) in the IQ domain in the C-terminal tail of these channels. Cav1.2 channels are arranged in cluster of eight, on average, in the cell membrane. When calcium ions bind to calmodulin, which in turn binds to a Cav1.2 channel, it allows the Cav1.2 channels within a cluster to interact with each other. This results in channels working cooperatively when they open at the same time to allow more calcium ions to enter and then close together to allow the cell to relax. Ca1

Clinical significance

Mutation in the CACNA1C gene, the single-nucleotide polymorphism located in the third intron of the Cav1.2 gene, are associated with a variant of

Long QT syndrome Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, ...

called Timothy's syndrome and more broadly with other CACNA1C-related disorders, and also with

Brugada syndrome Brugada syndrome (BrS) is a genetic disorder in which the electrical activity of the heart is abnormal due to channelopathy. It increases the risk of abnormal heart rhythms and sudden cardiac death. Those affected may have episodes of syn ...

. Large-scale genetic analyses have shown the possibility that CACNA1C is associated with

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

* and subsequently also with

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...

. Also, a CACNA1C risk allele has been associated to a disruption in brain connectivity in patients with bipolar disorder, while not or only to a minor degree, in their unaffected relatives or healthy controls.

Interactive pathway map

References

External links

GeneReviews/NIH/NCBI/UW entry on Brugada syndrome
*
GeneReviews/NIH/NCBI/UW entry on Timothy Syndrome
{{Ion channels, g1 Ion channels Biology of bipolar disorder