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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Nervous brain       highly Visual eye retina       Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Visual Muller 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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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