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FLASH GENE

Symbol

SLC6A4

contributors: mct - updated : 18-05-2016

HGNC name	solute carrier family 6 (neurotransmitter transporter, serotonin), member 4
HGNC id	11050

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	12 transmembrane segments (12TM)
	three Cys AAs on the second external loop, and disulfide bond formation between two AAs, Cys-200 and Cys-209, is required for SLC6A4 folding, surface expression, and transport activity
	EL4 (Extracellular Loop 4) has an important role in controlling the conformational equilibrium of SLC6A4
	C terminus harbors the binding site for the coat protein complex II (COPII) cargo-binding protein SEC24 , having a role in the folding of SLC6A4 and C-terminal domain recruits both the catalytic and regulatory subunits of the Ca(2+)-activated protein phosphatase calcineurin (PPP3CA)

secondary structure

alpha-helices

conjugated

GlycoP

HOMOLOGY

interspecies	homolog to murine Slc6a4
	homolog to C.elegans T23G5.5

Homologene

FAMILY	solute carrier family 6, 5-hydroxytryptamine, serotonin
	sodium:neurotransmitter symporter (SNF) family

CATEGORY

transport carrier

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic

basic FUNCTION	terminating the action of serotonin by its high affinity sodium-dependent reuptake into presynaptic terminals
	exquisitely sensitive to the cholesterol content of membranes
	potentially playing a role in heart valve development and disease
	membrane-bound transporter of serotonin that influences extracellular levels of this neurotransmitter
	involved in the modulation of activity-dependent mechanisms during the wiring of sensory circuits
	plays a crucial role in synaptic neurotransmission by retrieving released serotonin
	SLC6A3, SLC6A2, SLC6A4 facilitate the homeostatic balance of neurotransmitters in the synaptic cleft and thus, play a fundamental role in regulating neuronal activity
	regulates the extracellular concentration of serotonin, influencing neurotransmission
	is responsible for the termination of synaptic serotonergic signaling
	might disrupt efferocytosis and contribute to the pathogenesis of autoimmune and chronic inflammatory diseases
	plays a critical role in regulating serotonin signaling by mediating reuptake of serotonin from the extracellular space
	terminates serotonergic neurotransmission by performing reuptake of released serotonin, and is the primary target for antidepressants

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

active transport

text	sodium/chlorine Na+/Cl- coupled transporter of serotonin

PATHWAY

metabolism

signaling

neurotransmission

a component

INTERACTION

DNA

RNA

small molecule	metal binding,
	Na+
	Cl-

protein	interactions with ITGB3 playing a role in autism etiology and in serotonin level determination
	interacting with ROBO1, ROBO2
	important interactive relationship between SLC6A4 and the PDGFRB in the production of pulmonary artery smooth muscle cell proliferation triggered by PDGF that may be important in pulmonary hypertension (PH)
	interaction between SLC6A4 and the Secretory Carrier Membrane Protein 2 (SCAMP2)
	interacting with SEC24C (can only exit the ER by recruiting SEC24C)
	involvement of ERP44 in maturation of SLC6A4
	ERP44 together with ERO1A plays an important role in disulfide formation of SLC6A4, which may be a prerequisite step for the assembly of SLC6A4 molecules in oligomeric form
	utilizes ERP44 as well as its partner ERO1A, an oxidoreductase, in the disulfide bond formation process
	novel role of HDAC2 as a regulator of SLC6A4 gene expression in intestinal epithelial cells
	IL10 modulates SLC6A4 activity and expression in intestinal epithelial cells, depending on its extracellular conditions
	impairment of SLC6A4 may affect BDNF expression throughout postnatal development
	ITGB3 is a modulator of serotonergic systems via genetic interactions with the 5-HT transporter gene (SLC6A4)
	physical association of SLC6A4 with PPP3CA is promoted by PPP3CA activity
	TGFB1 increased the association of SLC6A4 with the soluble STX3 and promoted exocytosis of SLC6A4
	is epigenetically downregulated by HDAC1 in several types of cancer
	SLC6A4 associates with SLC1A5, co-expressed with SLC6A4 in serotonergic neurons and involved in the transport of small neutral amino acids across the plasma membrane

cell & other

REGULATION

Other	psychomotor stimutants such as amphetamines,cocaine or antidepressant
	is constitutively internalized and that the internalized transporter is sorted mainly to degradation

ASSOCIATED DISORDERS

corresponding disease(s)

Susceptibility

to sudden infant death a possible association to bipolar affective disorder and personality traits in a primarily female population sample susceptibility gene for high cholesterol and heart disease susceptibility to major depression, to attention deficit hyperactivity disorder, to autism and rigid-compulsive behaviors to obsessive-compulsive disorder(OCD)

Variant & Polymorphism other	some evidence of allelic variation modulating anxiety-related traits
	promoter polymorphism increasing the risk of sudden infant death (L/L)
	L(A) allele was twofold overtransmitted to the patients with OCD
	a 44-bp insertion/deletion polymorphism in the upstream regulatory region (5-HTTLPR) and a VNTR polymorphism in the second intron (Stin2) increasing the risk of SIDS

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed psychiatry autism   major therapeutic target in autism psychiatry bipolar disorder   common targets of drugs extensively used for the treatment of multiple different pathologies, ranging from anorexia, depression, anxiety and other psychiatric as well as neurological disorders to gastrointestinal and uro-genital dysfunctions

ANIMAL & CELL MODELS

Sert(-/-) rats show decreased brain-derived neurotrophic factor (Bdnf) expression, as well as reduced levels of transcription factor regulating the neurotrophin transcription