Caveolin-3 is a protein that in humans is encoded by the CAV3 gene. [5] [6] [7] 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.
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. [7]
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. [7] [8]
Caveolin 3 has been shown to interact with a range of different proteins, including, but not limited to:
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. [13]
Caveolin-3 is one of three isoforms of the protein caveolin. [14] Caveolin-3 is concentrated in the caveolae of myocytes, and modulates numerous metabolic processes including: nitric oxide synthesis, cholesterol metabolism, and cardiac myocytes contraction. [14] [15] [16] There are many proteins that associate with caveolin-3, including ion channels and exchangers. [14] [17] [18] [19] [20] [21] [22] [23]
In cardiac myocytes, caveolin-3 negatively regulates ATP-dependent potassium channels (KATP) localized in caveolae. [18] KATP channel opening decreases significantly when interacting with caveolin-3; other isoforms of caveolin do not show this type of effect on KATP channels. The amount of KATP 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. [18]
Caveolin-3 associates with the cardiac sodium-calcium exchanger (NCX) in caveolae of cardiac myocytes. [14] [24] This association occurs predominately in areas proximate to the peripheral membrane of cardiac myocytes. [24] Interactions between caveolin-3 and cardiac NCX influence NCX-regulation of cellular signaling factors and excitation of cardiac myocytes. [14]
Caveolin-3 influences the opening of L-Type calcium channels (LTCC) which play a role in cardiac myocyte contraction. [17] Disruption of interactions between caveolin-3 and its associated binding proteins has been shown to affect LTCC. [17] Specifically, disruption of caveolin-3 decreases the basal and b2-adrenergic-stimulated opening probabilities of LTCC. [17] This occurs by changing the PKA-mediated phosphorylation of caveolin-3-associated binding proteins, causing negative down-stream effects on LTCC activity. [17]
Alterations in caveolin-3 expression have been implicated in the altered expression and regulation of numerous signaling molecules involved in cardiomyopathies. [21] 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. [21] [25] Normal caveolin-3 expression under conditions of stress increases cardiac cellular levels of ANP, maintaining cardiac homeostasis. [21] Mutations have been identified in the caveolin-3 gene that result in cardiomyopathies. [20] Several of these mutations influence caveolin-3 function by reducing the expression of its cell-surface domains. [19] Mutations resulting in loss-of-function of caveolin-3 cause cardiac myocyte hypertrophy, dilation of the heart, and depression of fractional shortening. [22] [23] Knockout of caveolin-3 genes are sufficient to induce these manifestations. [25] 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. [22] [23] Overexpression of caveolin-3 leads to the development of cardiomyopathy, resulting in degeneration of cardiac tissue and manifesting pathologies due to the associated degeneration. [19]
In biology, caveolae, which are a special type of lipid raft, are small invaginations of the plasma membrane in the cells of many vertebrates. They are the most abundant surface feature of many vertebrate cell types, especially endothelial cells, adipocytes and embryonic notochord cells. They were originally discovered by E. Yamada in 1955.
In molecular biology, caveolins are a family of integral membrane proteins that are the principal components of caveolae membranes and involved in receptor-independent endocytosis. Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signaling molecules. They also induce positive (inward) membrane curvature by way of oligomerization, and hairpin insertion. Various classes of signaling molecules, including G-protein subunits, receptor and non-receptor tyrosine kinases, endothelial nitric oxide synthase (eNOS), and small GTPases, bind Cav-1 through its 'caveolin-scaffolding domain'.
Dysferlin also known as dystrophy-associated fer-1-like protein is a protein that in humans is encoded by the DYSF gene. Dysferlin is linked with plasma membrane repair., stabilization of calcium signaling and the development of the T-tubule system of the muscle A defect in the DYSF gene, located on chromosome 2p12-14, results in several types of muscular dystrophy; including Miyoshi myopathy (MM), Limb-girdle muscular dystrophy type 2B (LGMD2B) and Distal Myopathy (DM). A reduction or absence of dysferlin, termed dysferlinopathy, usually becomes apparent in the third or fourth decade of life and is characterised by weakness and wasting of various voluntary skeletal muscles. Pathogenic mutations leading to dysferlinopathy can occur throughout the DYSF gene.
Desmoplakin is a protein in humans that is encoded by the DSP gene. Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell contacts. In cardiac muscle, desmoplakin is localized to intercalated discs which mechanically couple cardiac cells to function in a coordinated syncytial structure. Mutations in desmoplakin have been shown to play a role in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, where it may present with acute myocardial injury; striate palmoplantar keratoderma, Carvajal syndrome and paraneoplastic pemphigus.
Paxillin is a protein that in humans is encoded by the PXN gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutations in PXN as well as abnormal expression of paxillin protein has been implicated in the progression of various cancers.
Caveolin-1 is a protein that in humans is encoded by the CAV1 gene.
RAS p21 protein activator 1 or RasGAP, also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:
Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration.
Heat shock protein beta-8 is a protein that in humans is encoded by the HSPB8 gene.
Myocyte-specific enhancer factor 2A is a protein that in humans is encoded by the MEF2A gene. MEF2A is a transcription factor in the Mef2 family. In humans it is located on chromosome 15q26. Certain mutations in MEF2A cause an autosomal dominant form of coronary artery disease and myocardial infarction.
5'-AMP-activated protein kinase subunit gamma-2 is an enzyme that in humans is encoded by the PRKAG2 gene.
Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (SERCA1) also known as Calcium pump 1, is an enzyme that in humans is encoded by the ATP2A1 gene.
Alpha-7 integrin is a protein that in humans is encoded by the ITGA7 gene. Alpha-7 integrin is critical for modulating cell-matrix interactions. Alpha-7 integrin is highly expressed in cardiac muscle, skeletal muscle and smooth muscle cells, and localizes to Z-disc and costamere structures. Mutations in ITGA7 have been associated with congenital myopathies and noncompaction cardiomyopathy, and altered expression levels of alpha-7 integrin have been identified in various forms of muscular dystrophy.
Telethonin, also known as Tcap, is a protein that in humans is encoded by the TCAP gene. Telethonin is expressed in cardiac and skeletal muscle at Z-discs and functions to regulate sarcomere assembly, T-tubule function and apoptosis. Telethonin has been implicated in several diseases, including limb-girdle muscular dystrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy and idiopathic cardiomyopathy.
Delta-sarcoglycan is a protein that in humans is encoded by the SGCD gene.
Paired mesoderm homeobox protein 2A is a protein that in humans is encoded by the PHOX2A gene.
A kinase anchor protein 1, mitochondrial is an enzyme that in humans is encoded by the AKAP1 gene.
Myozenin-1 is a protein that in humans is encoded by the MYOZ1 gene.
Caveolin-2 is a protein that in humans is encoded by the CAV2 gene.
Ankyrin-3 (ANK-3), also known as ankyrin-G, is a protein from ankyrin family that in humans is encoded by the ANK3 gene.
