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FLASH GENE
Symbol SLC12A5 contributors: mct/npt/pgu - updated : 24-10-2015
HGNC name solute carrier family 12, (potassium-chloride transporter) member 5
HGNC id 13818
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • cytoplasmic C terminus, between residues 929 and 1043 rich in prolines, serines, and charged residues
  • large extracellular loop between transmembrane segments 5 and 6
  • encompasses two predicted PEST sequences
  • 12 transmembrane domains flanked by two intracellular C- termini
  • evolutionary extremely conserved beta1 strand, which links the transmembrane domain to a C-terminal dimerization interface
  • a 15 AA region near the end of the C terminus, unique to SLC12A5 (the ISO domain), is required for SLC12A5 to cotransport K(+) and Cl(-) out of the neuron under isotonic conditions (
  • mono polymer homomer , heteromer , heptamer
    HOMOLOGY
    Homologene
    FAMILY
  • SLC12A transporter family
  • CATEGORY transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
    basic FUNCTION
  • integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway
  • mediating electroneutral potassium-chloride cotransport in mature neurons, transport occuring under isotonic conditions
  • plays a crucial role in determining intracellular chloride activity and thus the neuronal response to gamma-aminobutyric acid and glycine
  • regulate epithelial ion transport and osmotic homeostasis
  • key factor in the maturation of dendritic spines
  • acts as a synchronizing factor in the functional development of glutamatergic and GABAergic synapses in cortical neurons and networks
  • play an important role in the maintenance of cellular homeostasis
  • neuron-specific K-Cl cotransporter, inducing a developmental shift to render GABAergic transmission from depolarizing to hyperpolarizing
  • plays a major role in maintaining intracellular Cl− concentration in neurons below its electrochemical equilibrium potential, thus favoring robust GABA hyperpolarizing or inhibitory responses
  • likely through interactions with the actin cytoskeleton, hinders transmembrane protein diffusion, and thereby contributes to their confinement within dendritic spines
  • appears to mediate a functional cross-talk between synaptic excitation and inhibition in neurons
  • constrains protein diffusion in dendritic spines, likely via interactions with submembrane proteins and cytoskeleton rather than by nonspecific molecular crowding
  • role in excitatory synaptogenesis through a mechanism that is independent of its ion transport function
  • its activity is required for hyperpolarizing action of GABA and glycine
  • neuron-specific K(+)-Cl(-) cotransporter that is essential for Cl(-) homeostasis and fast inhibitory synaptic transmission in the mature CNS
  • is a neuron-specific K+-Cl- cotransporter essential for establishing the Cl- gradient required for hyperpolarizing inhibition in the central nervous system (CNS)
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • EGR4 is an important component in the mechanism of BDNF-dependent SLC12A5 gene regulation via the ERK1/2 pathway in immature neurons
  • SLC12A5-mediated transport therefore plays a pivotal role in neuronal inhibition
  • interacting with NETO2 (NETO2 is required to maintain the normal abundance of SLC12A5 and specifically associates with the active oligomeric form of the transporter)
  • in addition to its conventional role as a cell adhesion molecule to regulate GABAergic synaptogenesis, NLGN2 also regulates SLC12A5 to modulate GABA functional switch and even glutamatergic synapses
  • WNK1-regulated changes in SLC12A5 phosphorylation contribute to the developmental excitatory-to-inhibitory GABA sequence
  • neuron-specific cation-chloride cotransporter that is essential for hyperpolarizing GABAergic signaling and formation of cortical dendritic spines
  • WNK1 and WNK4 are the targets for the KLHL3-CUL3 complex and modulate the activity of SLC12A5 by means of intermediary Ste20-type kinases known as STK39 or OSR1
  • can physically associate with the potassium-chloride cotransporter protein, SLC12A5
  • cell & other
    REGULATION
    activated by IGF1 (plays an important role in IGF1 receptor signaling to promote growth and spread of breast cancer cells)
    induced by activation ofHTR2A that upregulates the function of the neuronal K-Cl cotransporter SLC12A5
    inhibited by furosemide and bumetanide.
    Other PKC-dependent phosphorylation of SLC12A5 may play a central role in modulating its functional expression (by an increased cell surface stability) in the brain and the strength of synaptic inhibition
    tyrosine phosphorylation regulates the membrane trafficking of the potassium chloride co-transporter SLC12A52
    ASSOCIATED DISORDERS
    corresponding disease(s) EIEE34
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    resulted in fewer mature spontaneously active spinal neurons, more immature silent neurons, and disrupted motor activity
    constitutional     --low  
    in mature neurons in several pathological conditions, including epilepsy and neuropathic pain
    constitutional     --low  
    in the postmortem hippocampus of patients with schizophrenia
    constitutional     --low  
    reduced SLC12A5/SLC12A2 ratio in the cerebrospinal fluid of Rett Syndrome patients, suggesting a disturbed process of GABAergic neuronal maturation
    Susceptibility to febrile seizures
    Variant & Polymorphism other KCC2-R952H is a bona fide susceptibility variant for febrile seizures (pMID: 24668262)
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurology  
    up-regulation of SLC12A5 function by targeting HTR2A, has therapeutic potential in the treatment of neurological disorders involving altered chloride homeostasis
    ANIMAL & CELL MODELS
    two neuron-specific isoforms (KCC2a and KCC2b) in mice. Kcc2a expression in the absence of Kcc2b is presumably sufficient to support vital neuronal functions in the brain stem and spinal cord