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FLASH GENE
Symbol TRPC6 contributors: mct/shn/pgu - updated : 15-03-2016
HGNC name transient receptor potential cation channel, subfamily C, member 6
HGNC id 12338
Corresponding disease
FSGS2 focal segmental glomerulosclerosis 2
Location 11q22.1      Physical location : 101.322.295 - 101.454.659
Synonym name
  • transient receptor potential channel 6
  • transient receptor protein 6
  • melastatin-like transient receptor potential 6
  • short transient receptor potential channel 6
  • Synonym symbol(s) TRP6, TRP-6, FSGS2, FLJ11098, FLJ14863
    DNA
    TYPE functioning gene
    STRUCTURE 132.37 kb     13 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    LOC390247 11 similar to peptidylprolyl isomerase A (cyclophilin A) LOC338734 11q22.1 similar to Oligophrenin 1 LOC387806 11 similar to SI:bZ1P14.10 (novel protein similar to human oligophrenin 1 (OPHN1)) FLJ32810 11q22.2 hypothetical protein FLJ32810 AD031 11q22.2 AD031 protein PGR 11q22 progesterone receptor TRPC6 11q21-q22 transient receptor potential cation channel, subfamily C, member 6 ANGPTL5 11q22.2 angiopoietin-like 5 MGC13040 11q22.2 hypothetical protein MGC13040 YAP1 11q13 Yes-associated protein 1, 65kDa LOC120318 11q22.2 similar to 40S ribosomal protein S6 (Phosphoprotein NP33) BIRC3 11q25 baculoviral IAP repeat-containing 3 BIRC2 11q22 baculoviral IAP repeat-containing 2 PORIMIN 11q22.1 Homo sapiens pro-oncosis receptor inducing membrane injury gene (PORIMIN), mRNA. MMP7 11q22.2-q22.3 matrix metalloproteinase 7 (matrilysin, uterine) MMP20 11q22.2-q22.3 matrix metalloproteinase 20 (enamelysin) MMP27 11q24 matrix metalloproteinase 27 MMP8 11q22.2-q22.3 matrix metalloproteinase 8 (neutrophil collagenase)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    13 - 4612 106.1 931 - 1998 9925922
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Hearing/Equilibriumearinnercochlea   Homo sapiens
    Nervousbrain   moderately Homo sapiens
     gangliasensory ganglia    Homo sapiens
    Respiratorylung   predominantly Homo sapiens
    Urinarykidneytubule    Homo sapiens
     kidneynephron    Homo sapiens
     kidneynephronrenal capsuleglomerulus  Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticerythrocyte
    Blood/Hematopoieticerythroid
    Hearing / Equilibriumcochlea cell Homo sapiens
    Hearing / Equilibriumhair cell receptor Homo sapiens
    Reproductivespermatocyte
    Urinarymesangial cell Homo sapiens
    Urinarypodocyte Homo sapiens
    Urinarytubular cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion sperm
    at STAGE
    physiological period embryo
    Text kidney
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • cytoplasmic N terminus with four ankyrin repeats
  • a coiled-coil structure
  • six transmembrane segments
  • a cytoplasmic C terminus with a dystrophin (coiled-coil) domain
  • a highly conserved TRP (EWKFHR) domain
  • conjugated GlycoP , PhosphoP
    HOMOLOGY
    interspecies ortholog to Drosophila store-operated calcium channel (Soc)
    ortholog to Trpc6, Mus musculus
    ortholog to Trpc6 , Rattus norvegicus
    ortholog to trpc6, Danio rerio
    ortholog to TRPC6, Pan troglodytes
    Homologene
    FAMILY
  • Ca2+ conductive channel in TRPC family
  • CATEGORY receptor membrane
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,cytosolic
    text
  • mostly associated to the surface of the spermatogenic cells
  • localized to excitatory synapses
  • translocates to the plasma membrane upon stimulation and remains there as long as the stimulus is present
  • basic FUNCTION
  • non selective cation channel enabling Ca2+ influx into cells
  • supposed to have a fundamental role in the regulation of smooth muscle tone in blood vessels and lung (
  • may influence sperm motility
  • calcium (Ca2+) and magnesium (Mg2+) conducting channel, during proliferation of human osteoblasts
  • its activation is sufficient to induce keratinocyte differentiation similar to the physiological stimulus [Ca2+]
  • playing an essential role for proper regulation of podocyte structure and function, by its channel activity at the slit diaphragm
  • Ca2+-permeable channel, activation of which is linked to a G protein-coupled receptor or receptor tyrosine kinase signaling pathway
  • playing a unique and indispensable role in acute hypoxic pulmonary vasoconstriction
  • required for BDNF-mediated neuronal protection and protects cerebellar granule neurons against serum deprivation
  • might act as an important mediator for sensing the extracellular signals that affect synaptic and behavioral plasticity
  • involvement of TRPC6-mediated Ca2+ entry in the RHOA-dependent regulation of actin cytoskeleton has been demonstrated in endothelial cells and kidney podocytes
  • playing an essential role for angiotensin II-induced cardiac hypertrophy
  • contributes to the Ca(2+) leak of human erythrocytes
  • promotes hippocampal neuron dendritic growth
  • regulates TRPC3 activation by erythropoietin by modulation of signaling mechanisms, including reduced interaction of TRPC6 with phospholipase C gamma and Epo-R
  • may be involved in VEGF-mediated angiogenesis
  • participates both in cacapitative Ca2+ entry and non capacitative Ca2+ entry through its interaction with the Orai-STIM1 complex or TRPC3 respectively
  • invovled in the development of gastric cancers through the regulation of Ca2+ elevation which is essential for G2/M transition
  • necessary mediator of pathologic cardiac hypertrophy, in part through a calcineurin/NFAT signaling pathway
  • TRPC5 and TRPC6 are antagonistic regulators of actin remodeling and cell motility in fibroblasts and kidney podocytes
  • TRPC5 and TRPC6 channels are now known as the Ca(2+) influx pathways for nonselective, cationic current in podocytes
  • upregulation of TRPC6 is involved in the Ca2+ signaling and actin assembly in human mesangial cells (MCs) after chronic hypoxia
  • role of TRPC6 in actin assembly and reorganization in response to chronic hypoxia
  • TRPC3 and TRPC6 are thus required for the normal function of cells involved in touch and hearing, and are potential components of mechanotransducing complexes
  • dual and context dependent role of TRPC6 in podocytes where acute activation protects from complement-mediated damage, but chronic overactivation leads to focal segmental glomerulosclerosis
  • is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response
  • TRPC6 channel translocation into phagosomal membrane augments phagosomal function
  • may protect renal ischemia-reperfusion injury through inhibiting necroptosis of renal tubular epithelial cells
  • CELLULAR PROCESS cell migration & motility
    PHYSIOLOGICAL PROCESS
    text regulation of intracellular calcium concentration
    PATHWAY
    metabolism
    signaling
    a component comprised of homo- or heterotetramers between TRPC3/6/7
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • TRPC3 and TRPC7 (
  • transient receptor potential channel 2, TRPC2 (
  • SH2 domain of Fyn (
  • myxovirus (influenza) resistance A, MxA (
  • ORAI calcium release-activated calcium modulator 1, ORAI1 (
  • promoted dendritic growth via the CAMK4-CREB pathway
  • is in a molecular complex with RhoA
  • phospholipase C (PLC)-gamma1 and cytoplasmic domain of nephrin (
  • insulin increases generation of ROS in part through activation of NADPH oxidases, and this step contributes to modulation of podocyte TRPC6 channels
  • PI3K/PTEN pathway plays an important role in the translocation of TRPC6 to the plasma membrane and may thus have a significant impact on Ca2+ signaling in cells that endogenously express TRPC6
  • TRPC6 down-regulation could contribute to the antiproteinuric effect of vitamin D
  • involvement of three basic residues in the integrative overlapping binding site for S100A1 on the C tail of TRPC6
  • function of NOD2 for the regulation of TRPC6 channels, suggesting that TRPC6-dependent Ca(2+) signaling is one of the critical signal transduction pathways that links innate immunity mediator NOD2 to podocyte injury
  • PRKG1 is a potent negative modulator of cardiac systolic mechanosignaling that requires TRPC6 as the target effector
  • redundant role of PLCE1-mediated TRPC6 activation at least in podocytes
  • locally generated SDC4 may play a role in regulating TRPC6 channels, and may contribute to glomerular pathology
  • evidence for a role of immunophilins, including FKBP3 and FKBP8, in Non-capacitative calcium entry (NCCE) mediated by TRPC6
  • lysophosphatidylcholine (lysoPC) induces CALM1 phosphorylation at Tyr(99) by a Src family kinase and phosphorylated CALM1 activates PI3K to produce PIP3, which promotes TRPC6 translocation to the cell membrane
  • lipid oxidation products, including lysophosphatidylcholine (lysoPC), activate canonical TRPC6 channels, and the subsequent increase in intracellular Ca2+ leads to TRPC5 activation
  • cell & other
    REGULATION
    activated by diacylglycerol (DAG) generated by G protein-coupled receptors (GPCR)/Gαq/phospholipase C signaling
    N-linked protein glycosylation
    receptor tyrosine kinases or G protein-coupled receptors
    cysteine oxidation-dependent pathway which not only stimulates the TRPC6 channel by itself but also sensitizes the channels to diacylglycerol and promotes TRPC6 trafficking to the cell surface
    PLC-gamma1 and nephrin (
    diacylglycerol (
    induced by insulin that increases the expression of TRPC6 channels in podocytes by activation of the calcineurin-dependent pathway
    Phosphorylated by Src family PTKs (
    Other seems to be non-activated by calcium store depletion, independently of protein kinases C
    probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinase
  • PI3K/PTEN pathway plays an important role in TRPC6 activation
  • ASSOCIATED DISORDERS
    corresponding disease(s) FSGS2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    upregulated in gastric cancer epithelial cells
    constitutional       gain of function
    is involved in Ca(2+) signaling and actin reorganization in podocytes after oxygen glucose deprivation (OGD)
    Susceptibility
  • to idiopathic membranous glomerulopathy (iMN)
  • Variant & Polymorphism SNP
  • a SNP in the promoter region and a missense variant in exon 4 may be putative causal variants for infantile hypertrophic pyloric stenosis
  • 254C->G SNP may predispose individuals to an increased risk of idiopathic pulmonary arterial hypertension
  • genetic variants in TRPC6 might affect susceptibility to development or progression of iMN
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    diabete  
    newly-identified ROS/TRPC6 pathway will pave the way to new, promising therapeutic strategies to target kidney diseases such as diabetic nephropathy
    respiratorylung 
    manipulation of TRPC6 function may thus offer a therapeutic strategy for the control of pulmonary hemodynamics and gas exchange
    dermatologyskin 
    activation by hyperforin may represent a new innovative therapeutic strategy in skin disorders characterized by altered keratinocyte differentiation
    cancerbrain 
    key mediator of tumor growth of glioblastoma multiforme (GBM) and may be a promising therapeutic target in the treatment of GBM
    cardiovascularaquiredheart failure
    . pharmacologic inhibitors of TRPC channels might be a strategy for attenuating local Ca2+ signals involved in pathologic cardiac hypertrophy or failure
    ANIMAL & CELL MODELS
  • in TRPC6-/- mice, a higher contractility in isolated tracheal and aortic rings was observed following application of the agonists methacholine and phenylephrine, respectively, as well as a reduced agonist-induced expiration rate (