Caveolin 3

CAV3
Identifiers
Aliases	CAV3, LGMD1C, LQT9, VIP-21, VIP21, caveolin 3, MPDT, RMD2
External IDs	OMIM: 601253; MGI: 107570; HomoloGene: 7255; GeneCards: CAV3; OMA:CAV3 - orthologs
Gene location (Human) Chr. Chromosome 3 (human) Band 3p25.3 Start 8,733,802 bp End 8,841,808 bp
Gene location (Mouse) Chr. Chromosome 6 (mouse) Band 6 E3|6 52.26 cM Start 112,436,466 bp End 112,449,833 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in muscle of thigh vastus lateralis muscle triceps brachii muscle Skeletal muscle tissue of rectus abdominis biceps brachii Skeletal muscle tissue of biceps brachii thoracic diaphragm gastrocnemius muscle deltoid muscle tibialis anterior muscle Top expressed in cardiac muscle tissue of left ventricle interventricular septum plantaris muscle soleus muscle extensor digitorum longus muscle temporal muscle masseter muscle thoracic diaphragm extraocular muscle triceps brachii muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transmembrane transporter binding protein C-terminus binding potassium channel inhibitor activity calcium channel regulator activity protein binding molecular adaptor activity sodium channel regulator activity connexin binding alpha-tubulin binding protein-containing complex binding enzyme binding nitric-oxide synthase binding structural molecule activity Cellular component cytoplasm membrane T-tubule dystrophin-associated glycoprotein complex cell surface Z discdkac endoplasmic reticulum membrane raft Golgi apparatus intracellular membrane-bounded organelle intercalated disc neuromuscular junction plasma membrane vesicle Golgi membrane sarcolemma caveola protein-containing complex integral component of plasma membrane focal adhesion Biological process myotube differentiation muscle contraction regulation of heart contraction muscle cell cellular homeostasis negative regulation of cardiac muscle hypertrophy negative regulation of membrane depolarization during cardiac muscle cell action potential regulation of membrane potential muscle organ development regulation of calcium ion import plasma membrane repair regulation of signaling membrane raft organization regulation of sodium ion transmembrane transporter activity positive regulation of microtubule polymerization cholesterol homeostasis triglyceride metabolic process negative regulation of cell size regulation of skeletal muscle contraction T-tubule organization regulation of ventricular cardiac muscle cell membrane depolarization heart trabecula formation glucose homeostasis actin filament organization cardiac muscle cell development regulation of branching involved in mammary gland duct morphogenesis ventricular cardiac muscle cell action potential detection of muscle stretch regulation of signal transduction by receptor internalization negative regulation of cell growth involved in cardiac muscle cell development negative regulation of MAP kinase activity cytoplasmic microtubule organization regulation of nerve growth factor receptor activity regulation of protein kinase B signaling negative regulation of potassium ion transmembrane transport regulation of p38MAPK cascade protein localization to plasma membrane plasma membrane organization regulation of membrane depolarization during cardiac muscle cell action potential negative regulation of sarcomere organization cell differentiation negative regulation of protein kinase activity nucleus localization regulation of heart rate negative regulation of protein localization to cell surface positive regulation of ubiquitin-dependent protein catabolic process negative regulation of MAPK cascade myoblast fusion regulation of calcium ion transmembrane transporter activity protein localization positive regulation of myotube differentiation positive regulation of caveolin-mediated endocytosis regulation of calcium ion transport endocytosis negative regulation of nitric-oxide synthase activity caveola assembly positive regulation of cytosolic calcium ion concentration regulation of transforming growth factor beta receptor signaling pathway negative regulation of potassium ion transmembrane transporter activity positive regulation of cell population proliferation negative regulation of calcium ion transport regulation of cardiac muscle contraction regulation of ventricular cardiac muscle cell membrane repolarization regulation of cardiac muscle cell action potential involved in regulation of contraction cellular response to organonitrogen compound Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 859 12391 Ensembl ENSG00000182533 ENSMUSG00000062694 UniProt P56539 P51637 RefSeq (mRNA) NM_033337 NM_001234 NM_007617 RefSeq (protein) NP_001225 NP_203123 NP_031643 Location (UCSC) Chr 3: 8.73 – 8.84 Mb Chr 6: 112.44 – 112.45 Mb PubMed search
Wikidata
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Caveolin-3 is a protein that in humans is encoded by the CAV3 gene. Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites.

Function

This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules.

Clinical significance

Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), HyperCKemia, distal myopathy or rippling muscle disease (RMD). Other mutations in Caveolin causes Long QT Syndrome or familial hypertrophic cardiomyopathy, although the role of Cav3 in Long QT syndrome has recently been disputed.

Interactions

Caveolin 3 has been shown to interact with a range of different proteins, including, but not limited to:

• DAG1,
• DYSF,
• EGFR, and
• RYR1.

Structure

Using transmission electron microscopy and single particle analysis methods, it has been shown that nine Caveolin-3 monomers assemble to form a complex that is toroidal in shape, ~16.5 nm in diameter and ~5.5 nm in height.

Cardiac physiology

Caveolin-3 is one of three isoforms of the protein caveolin. Caveolin-3 is concentrated in the caveolae of myocytes, and modulates numerous metabolic processes including: nitric oxide synthesis, cholesterol metabolism, and cardiac myocytes contraction. There are many proteins that associate with caveolin-3, including ion channels and exchangers.

Associations with ion channels

ATP-dependent potassium channels

In cardiac myocytes, caveolin-3 negatively regulates ATP-dependent potassium channels (K_ATP) localized in caveolae. K_ATP channel opening decreases significantly when interacting with caveolin-3; other isoforms of caveolin do not show this type of effect on K_ATP channels. The amount of K_ATP activation during times of biological stress influences the amount of cellular damage that will occur, thus regulation of caveolin-3 expression during these times influences the amount of cellular damage.

Sodium-calcium exchanger

Caveolin-3 associates with the cardiac sodium-calcium exchanger (NCX) in caveolae of cardiac myocytes. This association occurs predominately in areas proximate to the peripheral membrane of cardiac myocytes. Interactions between caveolin-3 and cardiac NCX influence NCX-regulation of cellular signaling factors and excitation of cardiac myocytes.

L-Type calcium channel

Caveolin-3 influences the opening of L-Type calcium channels (LTCC) which play a role in cardiac myocyte contraction. Disruption of interactions between caveolin-3 and its associated binding proteins has been shown to affect LTCC. Specifically, disruption of caveolin-3 decreases the basal and b₂-adrenergic-stimulated opening probabilities of LTCC. This occurs by changing the PKA-mediated phosphorylation of caveolin-3-associated binding proteins, causing negative down-stream effects on LTCC activity.

Implications in disease

Alterations in caveolin-3 expression have been implicated in the altered expression and regulation of numerous signaling molecules involved in cardiomyopathies. Disruption of caveolin-3 disturbs the structure of cardiac caveolae and blocks atrial natriuretic peptide (ANP) expression, a cardiac-related hormone involved in many functions including maintaining cellular homeostasis. Normal caveolin-3 expression under conditions of stress increases cardiac cellular levels of ANP, maintaining cardiac homeostasis. Mutations have been identified in the caveolin-3 gene that result in cardiomyopathies. Several of these mutations influence caveolin-3 function by reducing the expression of its cell-surface domains. Mutations resulting in loss-of-function of caveolin-3 cause cardiac myocyte hypertrophy, dilation of the heart, and depression of fractional shortening. Knockout of caveolin-3 genes are sufficient to induce these manifestations. Similarly, dominant-negative genotypes for caveolin-3 increase cardiac hypertrophy, whereas increased expression of caveolin-3 inhibits the ability of the heart to hypertrophy, implicating caveolin-3 as a negative regulator of cardiac hypertrophy. Overexpression of caveolin-3 leads to the development of cardiomyopathy, resulting in degeneration of cardiac tissue and manifesting pathologies due to the associated degeneration.

Further reading

• Figarella-Branger D, Pouget J, Bernard R, Krahn M, Fernandez C, Lévy N, Pellissier JF (2004). "Limb-girdle muscular dystrophy in a 71-year-old woman with an R27Q mutation in the CAV3 gene". Neurology. 61 (4): 562–4. doi:10.1212/01.wnl.0000076486.57572.5c. PMID 12939441. S2CID 40129179.
• Woodman SE, Sotgia F, Galbiati F, Minetti C, Lisanti MP (2005). "Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases". Neurology. 62 (4): 538–43. doi:10.1212/wnl.62.4.538. PMID 14981167.
• Li S, Okamoto T, Chun M, Sargiacomo M, Casanova JE, Hansen SH, Nishimoto I, Lisanti MP (1995). "Evidence for a regulated interaction between heterotrimeric G proteins and caveolin". J. Biol. Chem. 270 (26): 15693–701. doi:10.1074/jbc.270.26.15693. PMID 7797570.
• Tang Z, Scherer PE, Okamoto T, Song K, Chu C, Kohtz DS, Nishimoto I, Lodish HF, Lisanti MP (1996). "Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle". J. Biol. Chem. 271 (4): 2255–61. doi:10.1074/jbc.271.4.2255. PMID 8567687.
• Scherer PE, Lisanti MP (1997). "Association of phosphofructokinase-M with caveolin-3 in differentiated skeletal myotubes. Dynamic regulation by extracellular glucose and intracellular metabolites". J. Biol. Chem. 272 (33): 20698–705. doi:10.1074/jbc.272.33.20698. PMID 9252390.
• Venema VJ, Ju H, Zou R, Venema RC (1997). "Interaction of neuronal nitric-oxide synthase with caveolin-3 in skeletal muscle. Identification of a novel caveolin scaffolding/inhibitory domain". J. Biol. Chem. 272 (45): 28187–90. doi:10.1074/jbc.272.45.28187. PMID 9353265.
• Couet J, Sargiacomo M, Lisanti MP (1997). "Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities". J. Biol. Chem. 272 (48): 30429–38. doi:10.1074/jbc.272.48.30429. PMID 9374534.
• Biederer C, Ries S, Drobnik W, Schmitz G (1998). "Molecular cloning of human caveolin 3". Biochim. Biophys. Acta. 1406 (1): 5–9. doi:10.1016/S0925-4439(97)00095-1. PMID 9545514.
• Yamamoto M, Toya Y, Schwencke C, Lisanti MP, Myers MG, Ishikawa Y (1998). "Caveolin is an activator of insulin receptor signaling". J. Biol. Chem. 273 (41): 26962–8. doi:10.1074/jbc.273.41.26962. PMID 9756945.
• Sotgia F, Minetti C, Lisanti MP (1999). "Localization of the human caveolin-3 gene to the D3S18/D3S4163/D3S4539 locus (3p25), in close proximity to the human oxytocin receptor gene. Identification of the caveolin-3 gene as a candidate for deletion in 3p-syndrome". FEBS Lett. 452 (3): 177–80. doi:10.1016/S0014-5793(99)00658-4. PMID 10386585. S2CID 44686134.
• Carbone I, Bruno C, Sotgia F, Bado M, Broda P, Masetti E, Panella A, Zara F, Bricarelli FD, Cordone G, Lisanti MP, Minetti C (2000). "Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia". Neurology. 54 (6): 1373–6. doi:10.1212/wnl.54.6.1373. PMID 10746614. S2CID 74588429.
• Biederer CH, Ries SJ, Moser M, Florio M, Israel MA, McCormick F, Buettner R (2000). "The basic helix-loop-helix transcription factors myogenin and Id2 mediate specific induction of caveolin-3 gene expression during embryonic development". J. Biol. Chem. 275 (34): 26245–51. doi:10.1074/jbc.M001430200. PMID 10835421.
• Sotgia F, Lee JK, Das K, Bedford M, Petrucci TC, Macioce P, Sargiacomo M, Bricarelli FD, Minetti C, Sudol M, Lisanti MP (2001). "Caveolin-3 directly interacts with the C-terminal tail of beta -dystroglycan. Identification of a central WW-like domain within caveolin family members". J. Biol. Chem. 275 (48): 38048–58. doi:10.1074/jbc.M005321200. PMID 10988290.
• Herrmann R, Straub V, Blank M, Kutzick C, Franke N, Jacob EN, Lenard HG, Kröger S, Voit T (2001). "Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy". Hum. Mol. Genet. 9 (15): 2335–40. doi:10.1093/oxfordjournals.hmg.a018926. PMID 11001938.
• Hagiwara Y, Sasaoka T, Araishi K, Imamura M, Yorifuji H, Nonaka I, Ozawa E, Kikuchi T (2001). "Caveolin-3 deficiency causes muscle degeneration in mice". Hum. Mol. Genet. 9 (20): 3047–54. doi:10.1093/hmg/9.20.3047. PMID 11115849.
• de Paula F, Vainzof M, Bernardino AL, McNally E, Kunkel LM, Zatz M (2001). "Mutations in the caveolin-3 gene: When are they pathogenic?". Am. J. Med. Genet. 99 (4): 303–7. doi:10.1002/1096-8628(2001)9999:9999<::AID-AJMG1168>3.0.CO;2-O. PMID 11251997.
• Betz RC, Schoser BG, Kasper D, Ricker K, Ramírez A, Stein V, Torbergsen T, Lee YA, Nöthen MM, Wienker TF, Malin JP, Propping P, Reis A, Mortier W, Jentsch TJ, Vorgerd M, Kubisch C (2001). "Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease". Nat. Genet. 28 (3): 218–9. doi:10.1038/90050. PMID 11431690. S2CID 35194603.
• Matsuda C, Hayashi YK, Ogawa M, Aoki M, Murayama K, Nishino I, Nonaka I, Arahata K, Brown RH (2002). "The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle". Hum. Mol. Genet. 10 (17): 1761–6. doi:10.1093/hmg/10.17.1761. PMID 11532985.