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Reviewed, UniProtKB/Swiss-Prot Q13936 (CAC1C_HUMAN)

Last modified July 22, 2008. Version 100. Feed History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein namesRecommended name:
    Voltage-dependent L-type calcium channel subunit alpha-1C
Alternative name(s):
    Voltage-gated calcium channel subunit alpha Cav1.2
    Calcium channel, L type, alpha-1 polypeptide, isoform 1, cardiac muscle
Gene names
Name: CACNA1C
Synonyms: CACH2, CACN2, CACNL1A1, CCHL1A1
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length2221 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

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General annotation (Comments)

Function

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds.

Subunit structure

Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1, alpha-2, beta and delta subunits in a 1:1:1:1 ratio. The channel activity is directed by the pore-forming and voltage-sensitive alpha-1 subunit. In many cases, this subunit is sufficient to generate voltage-sensitive calcium channel activity. The auxiliary subunits beta and alpha-2/delta linked by a disulfide bridge regulate the channel activity. Interacts with CACNA2D4.

Subcellular location

Membrane; Multi-pass membrane protein.

Tissue specificity

Expressed in brain, heart, jejunum, ovary, pancreatic beta-cells and vascular smooth muscle. Overall expression is reduced in atherosclerotic vascular smooth muscle.

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 By similarity.

Post-translational modification

Phosphorylation by PKA activates the channel By similarity.

Involvement in disease

Defects in CACNA1C are the cause of Timothy syndrome (TS) [MIM:601005]. TS is a disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism.

Defects in CACNA1C are the cause of Brugada syndrome type 3 (BRS3) [MIM:611875]. BRS3 is 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 (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not reset.

Sequence similarities

Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. [View classification]

Sequence caution

AAA02500.2 sequence differs from that shown. Reason: Frameshift at position 1845.

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Binary interactions

With

Entry

#Exp.

IntAct

Notes

CABP1Q9NZU72EBI-1038838,EBI-907894
CALM1P621581EBI-1038838,EBI-397435

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Alternative products

This entry describes 33 isoforms produced by alternative splicing. [Align] [Select]

Notes: Additional isoforms seem to exist. Exons 8A, 21, 22, 31, 32, 33, 40B, 43A, 41A and 45 are alternatively spliced in a variety of combinations. Experimental confirmation may be lacking for some isoforms.
Isoform 1 (identifier: Q13936-1)

Also known as: HFCC; Fibroblast;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q13936-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1864-1897: ERHVPVCEDLELRRDSGSAGTQAHCLLLRRANPS → MHCCDMLDGG...PAGCTAPQHA
Isoform 3 (identifier: Q13936-3)

The sequence of this isoform differs from the canonical sequence as follows:
     372-391: VNDAVGRDWPWIYFVTLIII → MQDAMGYELPWVYFVSLVIF
Notes: Contains exon 8a.
Isoform 4 (identifier: Q13936-4)

The sequence of this isoform differs from the canonical sequence as follows:
     932-951: Missing.
Notes: Lacks exon 21.
Isoform 5 (identifier: Q13936-5)

The sequence of this isoform differs from the canonical sequence as follows:
     952-971: Missing.
Notes: Lacks exon 22.
Isoform 6 (identifier: Q13936-6)

The sequence of this isoform differs from the canonical sequence as follows:
     1297-1324: Missing.
Notes: Lacks exon 31.
Isoform 7 (identifier: Q13936-7)

The sequence of this isoform differs from the canonical sequence as follows:
     1325-1352: Missing.
Notes: Lacks exon 32.
Isoform 8 (identifier: Q13936-8)

The sequence of this isoform differs from the canonical sequence as follows:
     1353-1363: Missing.
Notes: Lacks exon 33.
Isoform 9 (identifier: Q13936-9)

The sequence of this isoform differs from the canonical sequence as follows:
     1618-1699: LRIKTEGNLE...KPSQRNALSL → LRETELSSQV...RGPHHPPLGF
Notes: Contains exon 40B and 43A.
Isoform 10 (identifier: Q13936-10)

The sequence of this isoform differs from the canonical sequence as follows:
     1623-1623: E → EEGPSPSEAHQGAEDPFRPA
Notes: Contains exon 41A.
Isoform 11 (identifier: Q13936-11)

Also known as: Alpha-1C.90;

The sequence of this isoform differs from the canonical sequence as follows:
     1864-1898: Missing.
Notes: Lacks exon 45.
Isoform 12 (identifier: Q13936-12)

Also known as: Alpha-1C.70;

The sequence of this isoform differs from the canonical sequence as follows:
     952-971: Missing.
     1297-1324: Missing.
     1864-1898: Missing.
Isoform 13 (identifier: Q13936-13)

Also known as: Alpha-1C.127;

The sequence of this isoform differs from the canonical sequence as follows:
     952-971: Missing.
     1325-1352: Missing.
     1623-1623: E → EEGPSPSEAHQGAEDPFRPA
     1864-1898: Missing.
Isoform 14 (identifier: Q13936-14)

Also known as: Alpha-1C.126;

The sequence of this isoform differs from the canonical sequence as follows:
     952-971: Missing.
     1297-1324: Missing.
     1363-1363: M → MGPSCSHPPLAVLTAPPVADGFQ
     1623-1623: E → EEGPSPSEAHQGAEDPFRPA
     1864-1898: Missing.
Isoform 15 (identifier: Q13936-15)

Also known as: Alpha-1C.125;

The sequence of this isoform differs from the canonical sequence as follows:
     952-971: Missing.
     1297-1324: Missing.
     1351-1363: Missing.
     1623-1623: E → EEGPSPSEAHQGAEDPFRPA
     1864-1898: Missing.
Isoform 16 (identifier: Q13936-16)

The sequence of this isoform differs from the canonical sequence as follows:
     1-29: Missing.
     372-391: VNDAVGRDWPWIYFVTLIII → MQDAMGYELPWVYFVSLVIF
     952-971: Missing.
     1325-1352: Missing.
Isoform 17 (identifier: Q13936-17)

The sequence of this isoform differs from the canonical sequence as follows:
     1-29: Missing.
     372-391: VNDAVGRDWPWIYFVTLIII → MQDAMGYELPWVYFVSLVIF
     952-971: Missing.
     1325-1352: Missing.
     1864-1898: Missing.
Isoform 18 (identifier: Q13936-18)

Also known as: HHT-1;

The sequence of this isoform differs from the canonical sequence as follows:
     1-29: Missing.
     372-391: VNDAVGRDWPWIYFVTLIII → MQDAMGYELPWVYFVSLVIF
     952-971: Missing.
     1325-1352: Missing.
     1864-1897: ERHVPVCEDLELRRDSGSAGTQAHCLLLRRANPS → MHCCDMLDGG...PAGCTAPQHA
Isoform 19 (identifier: Q13936-19)

Also known as: Alpha-1C.76;

The sequence of this isoform differs from the canonical sequence as follows:
     932-951: Missing.
     1297-1324: Missing.
     1353-1363: Missing.
     1864-1898: Missing.
Isoform 20 (identifier: Q13936-20)

Also known as: Alpha-1C.77;

The sequence of this isoform differs from the canonical sequence as follows:
     932-951: Missing.
     1297-1324: Missing.
     1864-1898: Missing.
Notes: Predominant isoform in atherosclerotic vascular smooth muscle cells.
Isoform 21 (identifier: Q13936-21)

Also known as: Alpha-1C.69;

The sequence of this isoform differs from the canonical sequence as follows:
     932-951: Missing.
     1325-1352: Missing.
     1864-1898: Missing.
Isoform 22 (identifier: Q13936-22)

Also known as: Alpha-1C.78;

The sequence of this isoform differs from the canonical sequence as follows:
     952-971: Missing.
     1325-1352: Missing.
     1864-1898: Missing.
Isoform 23 (identifier: Q13936-23)

Also known as: Alpha-1C.105;

The sequence of this isoform differs from the canonical sequence as follows:
     372-391: VNDAVGRDWPWIYFVTLIII → MQDAMGYELPWVYFVSLVIF
     932-951: Missing.
     1297-1324: Missing.
     1864-1898: Missing.
Isoform 24 (identifier: Q13936-24)

Also known as: Alpha-1C.71;

The sequence of this isoform differs from the canonical sequence as follows:
     952-971: Missing.
     1297-1324: Missing.
     1623-1623: E → EEGPSPSEAHQGAEDPFRPA
     1864-1898: Missing.
Isoform 25 (identifier: Q13936-25)

Also known as: Alpha-1C.73;

The sequence of this isoform differs from the canonical sequence as follows:
     952-971: Missing.
     1297-1324: Missing.
     1353-1363: Missing.
     1623-1623: E → EEGPSPSEAHQGAEDPFRPA
     1864-1898: Missing.
Isoform 26 (identifier: Q13936-26)

Also known as: Alpha-1C.86;

The sequence of this isoform differs from the canonical sequence as follows:
     932-951: Missing.
     1297-1324: Missing.
     1618-1699: LRIKTEGNLE...KPSQRNALSL → LRETELSSQV...RGPHHPPLGF
     1864-1898: Missing.
Notes: Not inhibited by calcium.
Isoform 27 (identifier: Q13936-27)

Also known as: Alpha-1C.72;

The sequence of this isoform differs from the canonical sequence as follows:
     932-951: Missing.
     1297-1324: Missing.
     1623-1623: E → EEGPSPSEAHQGAEDPFRPA
     1864-1898: Missing.
Isoform 28 (identifier: Q13936-28)

The sequence of this isoform differs from the canonical sequence as follows:
     1-29: Missing.
     372-391: VNDAVGRDWPWIYFVTLIII → MQDAMGYELPWVYFVSLVIF
     952-971: Missing.
     1297-1324: Missing.
     1353-1363: Missing.
     1864-1897: ERHVPVCEDLELRRDSGSAGTQAHCLLLRRANPS → MHCCDMLDGG...PAGCTAPQHA
Isoform 29 (identifier: Q13936-29)

Also known as: Alpha-1C.74;

The sequence of this isoform differs from the canonical sequence as follows:
     932-951: Missing.
     1297-1324: Missing.
     1353-1363: Missing.
     1623-1623: E → EEGPSPSEAHQGAEDPFRPA
     1864-1898: Missing.
Isoform 30 (identifier: Q13936-30)

Also known as: Alpha-1C.87;

The sequence of this isoform differs from the canonical sequence as follows:
     1297-1324: Missing.
     1864-1898: Missing.
Isoform 31 (identifier: Q13936-31)

Also known as: Alpha-1C.88;

The sequence of this isoform differs from the canonical sequence as follows:
     952-971: Missing.
     1864-1898: Missing.
Isoform 32 (identifier: Q13936-32)

Also known as: Alpha-1C.89;

The sequence of this isoform differs from the canonical sequence as follows:
     932-951: Missing.
     1353-1363: Missing.
     1864-1898: Missing.
Isoform 33 (identifier: Q13936-33)

Also known as: Alpha-1C.85;

The sequence of this isoform differs from the canonical sequence as follows:
     932-951: Missing.
     1297-1324: Missing.

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical view

Molecule processing

Chain1 – 22212221Voltage-dependent L-type calcium channel subunit alpha-1C

Regions

Topological domain1 – 124124Cytoplasmic Potential
Transmembrane125 – 14319S1 of repeat I Potential
Topological domain144 – 16017Extracellular Potential
Transmembrane161 – 18121S2 of repeat I Potential
Topological domain182 – 19312Cytoplasmic Potential
Transmembrane194 – 21219S3 of repeat I Potential
Topological domain213 – 23220Extracellular Potential
Transmembrane233 – 25119S4 of repeat I Potential
Topological domain252 – 27019Cytoplasmic Potential
Transmembrane271 – 29020S5 of repeat I Potential
Topological domain291 – 38090Extracellular Potential
Transmembrane381 – 40525S6 of repeat I Potential
Topological domain406 – 524119Cytoplasmic Potential
Transmembrane525 – 54319S1 of repeat II Potential
Topological domain544 – 55815Extracellular Potential
Transmembrane559 – 57820S2 of repeat II Potential
Topological domain579 – 5868Cytoplasmic Potential
Transmembrane587 – 60519S3 of repeat II Potential
Topological domain606 – 61510Extracellular Potential
Transmembrane616 – 63419S4 of repeat II Potential
Topological domain635 – 65319Cytoplasmic Potential
Transmembrane654 – 67320S5 of repeat II Potential
Topological domain674 – 72855Extracellular Potential
Transmembrane729 – 75325S6 of repeat II Potential
Topological domain754 – 900147Cytoplasmic Potential
Transmembrane901 – 91919S1 of repeat III Potential
Topological domain920 – 93516Extracellular Potential
Transmembrane936 – 95520S2 of repeat III Potential
Topological domain956 – 98732Cytoplasmic Potential
Transmembrane988 – 100619S3 of repeat III Potential
Topological domain1007 – 10137Extracellular Potential
Transmembrane1014 – 103219S4 of repeat III Potential
Topological domain1033 – 105119Cytoplasmic Potential
Transmembrane1052 – 107120S5 of repeat III Potential
Topological domain1072 – 116190Extracellular Potential
Transmembrane1162 – 118625S6 of repeat III Potential
Topological domain1187 – 123953Cytoplasmic Potential
Transmembrane1240 – 125819S1 of repeat IV Potential
Topological domain1259 – 127315Extracellular Potential
Transmembrane1274 – 129320S2 of repeat IV Potential
Topological domain1294 – 13018Cytoplasmic Potential
Transmembrane1302 – 132019S3 of repeat IV Potential
Topological domain1321 – 137252Extracellular Potential
Transmembrane1373 – 139119S4 of repeat IV Potential
Topological domain1392 – 141019Cytoplasmic Potential
Transmembrane1411 – 143020S5 of repeat IV Potential
Topological domain1431 – 149969Extracellular Potential
Transmembrane1500 – 152425S6 of repeat IV Potential
Topological domain1525 – 2221697Cytoplasmic Potential
Repeat111 – 408298I
Repeat510 – 756247II
Repeat887 – 1189303III
Repeat1226 – 1527302IV
Calcium binding1553 – 156412 By similarity