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FLASH GENE
Symbol KCNIP3 contributors: npt/mct - updated : 13-06-2017
HGNC name Kv channel interacting protein 3, calsenilin
HGNC id 15523
Location 2q11.1      Physical location : 95.963.071 - 96.051.824
Synonym name
  • Downstream Regulatory Element Antagonist Modulator
  • calsenilin, presenilin binding protein, EF hand transcription factor
  • A-type potassium channel modulatory protein 3
    • Synonym symbol(s) DREAM, KCHIP3, CSEN, MGC18289
    DNA
    TYPE functioning gene
    STRUCTURE 88.75 kb     9 Exon(s)
    regulatory sequence Binding site
    motif repetitive sequence
    text structure
  • presenilin binding site
  • repetitive sequence = CA repeat
    • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 - 2928 29.1 256 brain highly, bone marrow, kidney, salivary gland 2005 16112838
    exon 1a and exon 2
    8 - 2735 - 230 widely, colon, heart, kidney, pancreas, prostate, cerebellum 2005 16112838
    exon 1b, lacking exon 2
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Nervousbrain   highly
    Visualeyeretina    Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    VisualMuller cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal portion of KCNIP3 is required for binding to HK1, and a KCNIP3 construct lacking the first 94 N-terminal AAs fails to bind HK1
  • C-terminal structure (AAs 78-256) contains four EF-hand motifs arranged in a tandem linear array, similar to that seen in KCNIP1, recoverin, and other structures of the neuronal calcium sensor (NCS) branch of the calmodulin superfamily
    • secondary structure Ca+2-bound structure consists of five alpha-helices and one two-stranded antiparallel beta-sheet
    conjugated LipoP
    mono polymer homomer , polymer
    HOMOLOGY
    interspecies homolog to murine Kcnip3 (91.8pc)
    homolog to rattus Csen (93.0pc)
    Homologene
    FAMILY
  • recoverin family
  • neuronal Ca(2+) sensor superfamily of EF-hand proteins
    • CATEGORY regulatory , transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    intracellular,nuclear envelope
    text
  • by increase in intracellular calcium concentration, calsenilin was translocated into the nucleus
  • following proteasomal inhibition calsenilin accumulated in the endoplasmic reticulum (ER) and Golgi, while lysosomal inhibition had no effect on calsenilin localization
    • basic FUNCTION
  • calcium-dependent transcriptional repressor regulating PSEN2
  • plays an important role in calcium signaling
  • proteolytic processing and modulating K4 voltage gated potassium channel
  • EF-hand calcium-binding protein that binds to specific DNA sequences and regulates Ca2+-induced transcription of prodynorphin and c-fos genes
  • playing a role in the regulation of Ca2+-regulated secretion (Venn 2008)
  • regulates gene transcription and Kv potassium channels in neurons but has also been claimed to interact with presenilins, which are involved in the generation of beta-amyloid and in the regulation of the Ca(2+) content in the endoplasmic reticulum
  • involved in modulating pain
  • contributes to the increased sensitivity of CLN3 knock-down cells to cell death
  • in the nucleus, modulates gene transcription of target genes and interacts with several nucleoproteins
  • modulates TSHR activity through a direct protein-protein interaction that promotes coupling between the receptor and Galphas
  • functions as a negative regulator of the key memory factor CREB in a Ca(2+)-dependent manner
  • key regulator of memory and brain aging
  • KCNIP3 and KCNC1 channels are expressed and may play a significant role in Müller cell function in the retina
  • is a Ca(2+)-dependent transcriptional repressor highly expressed in neuronal cells
  • neuronal EF-hand protein, modulating pain, potassium channel activity, and binding PSEN1
  • interaction of KCNIP3 with HK1 may be important in the regulation of neuronal apoptosis
  • is a Ca(2+)-binding protein that binds DNA and represses transcription in a Ca(2+)-dependent manner
  • is a major master switch transcription factor that regulates the on/off status of specific activity-dependent gene expression programs that control synaptic plasticity, learning, and memory
    • CELLULAR PROCESS cell life, cell death/apoptosis
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS nervous system
    PATHWAY
    metabolism
    signaling signal transduction
  • ADCYAP1-KCNIP3 cascade is a new pathway to activate GFAP gene expression during astrocyte differentiation
    • a component
  • regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels
  • DREAM complex is key regulator of cell cycle regulated gene transcription and drives the expression of many gene products required for mitosis and cytokinesis
    • INTERACTION
    DNA
  • affinity for DNA is reduced upon binding to calcium and enhanced by binding to magnesium (binds to DNA in a calcium-dependent manner )
    • RNA
    small molecule metal binding,
  • ions Ca2+
    • protein
  • prodynorphin (inhibition of transcription)
  • PSEN1, PSEN2
  • interacting with KCND2 and KCND3
  • associating with KCND1
  • binding to the C-terminus of CLN3
  • binds and regulates the gating properties of potassium channels of the KCNC1 class
  • interacts with presenilin 1 (PSEN1) and presenilin 2 (PSEN2), represses gene transcription and binds to A-type voltage-gated potassium channels
  • GAS2L3 is a target gene of KCNIP3
  • key role of CANT1, and of the regulation of its gene by KCNIP3, in the control of protein synthesis and degradation
  • interaction of KCNIP3 with the important EF-hand protein, CALM1, and this interaction alters calcineurin (CN) activity
  • is an upstream of the gamma-secretase cleavage of NOTCH1
  • calcium-regulated pathway whereby GCM1-directed villous trophoblast differentiation is repressed by KCNIP3
  • in the presence of Ca2+, KCNIP3 interacts with HK1, a protein known to bind mitochondria and regulate apoptosis
  • bound to the promoter of the gene encoding TNFAIP3 to repress expression of this deubiquitinase that suppresses inflammatory NFKB1 signaling
  • association of PSEN1 carboxyl peptide (residues 445-467, HL9) with KCNIP3 is calcium dependent and stabilized by a cluster of three aromatic residues
    • cell & other
    REGULATION
    Other proteolytically cleaved by caspase-3
    its degradation is primarily mediated by the ubiquitin–proteasomal pathway (UPP) and impairment in the UPP may contribute to the involvement of calsenilin in disease-associated neurodegeneration
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in the brains of Alzheimer disease and epilepsy patients, and may be due in part to decreased degradation of calsenilin, and that the dysfunction of proteasomal activity but not lysosomal activity contributes to accumulation of calsenilin in the ER
    constitutional     --low  
    promotes the degeneration of retinal ganglion cells (RGCs), amacrine cells, and bipolar cells
    Susceptibility
    Variant & Polymorphism
    Candidate gene may represent feasible target for therapeutic intervention in Alzheimer disease
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Kcnip3 -/- mice displayed markedly reduced responses in models of acute thermal, mechanical, and visceral pain
  • mice lacking Kcnip3 had elevated levels of prodynorphin mRNA and dynorphin A peptides in the spinal cord, and the reduction of pain behaviors in Dream -/- mice was mediated through dynorphin-selective kappa-opiate receptors
  • Dream-deficient mice displayed persistent and unchecked A20 expression in response to endotoxin