CACNA1C
Domain
Each of the four internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments probably represent the voltage-sensor and are characterized by a series of positively charged amino acids at every third position.
Binding of intracellular calcium through the EF-hand motif inhibits the opening of the channel.
Function
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:12181424, PubMed:15454078, PubMed:15863612, PubMed:16299511, PubMed:17224476, PubMed:20953164, PubMed:23677916, PubMed:24728418, PubMed:26253506, PubMed:27218670, PubMed:29078335, PubMed:29742403, PubMed:30023270, PubMed:30172029, PubMed:34163037, PubMed:8099908). Mediates influx of calcium ions into the cytoplasm, and thereby triggers calcium release from the sarcoplasm (By similarity). Plays an important role in excitation-contraction coupling in the heart. Required for normal heart development and normal regulation of heart rhythm (PubMed:15454078, PubMed:15863612, PubMed:17224476, PubMed:24728418, PubMed:26253506). Required for normal contraction of smooth muscle cells in blood vessels and in the intestine. Essential for normal blood pressure regulation via its role in the contraction of arterial smooth muscle cells (PubMed:28119464). Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (Probable).
Isoform 12
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 13
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 14
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 15
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 16
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 17
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 18
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 19
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 20
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 21
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 22
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 23
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 24
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 25
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 26
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 27
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
Isoform 34
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
(Microbial infection) Acts as a receptor for Influenzavirus (PubMed:29779930). May play a critical role in allowing virus entry when sialylated and expressed on lung tissues (PubMed:29779930).
Involvement in disease
Timothy syndrome
TS
Disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism.
None
The disease is caused by variants affecting the gene represented in this entry.
Brugada syndrome 3
BRGDA3
A heart disease characterized by the association of Brugada syndrome with shortened QT intervals. Brugada syndrome is a tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset.
None
The gene represented in this entry may be involved in disease pathogenesis.
Long QT syndrome 8
LQT8
A form of long QT syndrome, a heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. LQT8 transmission pattern is consistent with autosomal dominant inheritance with incomplete penetrance.
None
The disease is caused by variants affecting the gene represented in this entry.
Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
NEDHLSS
An autosomal dominant disorder characterized by global developmental delay apparent from infancy, intellectual disability, poor or absent speech, behavioral abnormalities, and hypotonia with delayed walking or inability to walk. Additional features include epilepsy, mild skeletal defects, and non-specific dysmorphic features.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Phosphorylation by PKA at Ser-1981 activates the channel. Elevated levels of blood glucose lead to increased phosphorylation by PKA.
Sequence Similarities
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1C subfamily.
Tissue Specificity
Detected throughout the brain, including hippocampus, cerebellum and amygdala, throughout the heart and vascular system, including ductus arteriosus, in urinary bladder, and in retina and sclera in the eye (PubMed:15454078). Expressed in brain, heart, jejunum, ovary, pancreatic beta-cells and vascular smooth muscle. Overall expression is reduced in atherosclerotic vascular smooth muscle.
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Cell membrane
- Sarcolemma
- Multi-pass membrane protein
- Perikaryon
- Postsynaptic density membrane
- Cell projection
- Dendrite
- Cell membrane
- Sarcolemma
- T-tubule
- Colocalizes with ryanodine receptors in distinct clusters at the junctional membrane, where the sarcolemma and the sarcoplasmic reticulum are in close contact. The interaction between RRAD and CACNB2 promotes the expression of CACNA1C at the cell membrane.
Alternative names
CACH2, CACN2, CACNL1A1, CCHL1A1, CACNA1C, Voltage-dependent L-type calcium channel subunit alpha-1C, Voltage-gated calcium channel subunit alpha Cav1.2