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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	restricted

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 Endocrine neuroendocrine pituitary       Lymphoid/Immune spleen         Nervous brain       specific Visual eye

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed 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