Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6FGDLW)

• DOT Name: Sodium-dependent serotonin transporter (SLC6A4)
• Synonyms: SERT; 5HT transporter; 5HTT; Solute carrier family 6 member 4
• Gene Name: SLC6A4
• Related Disease: Autism spectrum disorder
• UniProt ID: SC6A4_HUMAN
• PDB ID: 5I6X; 5I6Z; 5I71; 5I73; 5I74; 5I75; 6AWN; 6AWO; 6AWP; 6AWQ; 6DZV; 6DZW; 6DZY; 6DZZ; 6VRH; 6VRK; 6VRL; 6W2B; 6W2C; 7LI6; 7LI7; 7LI8; 7LI9; 7LIA; 7LWD; 7MGW; 7TXT
• Pfam ID: PF03491 ; PF00209
• Sequence:
  METTPLNSQKQLSACEDGEDCQENGVLQKVVPTPGDKVESGQISNGYSAVPSPGAGDDTR
  HSIPATTTTLVAELHQGERETWGKKVDFLLSVIGYAVDLGNVWRFPYICYQNGGGAFLLP
  YTIMAIFGGIPLFYMELALGQYHRNGCISIWRKICPIFKGIGYAICIIAFYIASYYNTIM
  AWALYYLISSFTDQLPWTSCKNSWNTGNCTNYFSEDNITWTLHSTSPAEEFYTRHVLQIH
  RSKGLQDLGGISWQLALCIMLIFTVIYFSIWKGVKTSGKVVWVTATFPYIILSVLLVRGA
  TLPGAWRGVLFYLKPNWQKLLETGVWIDAAAQIFFSLGPGFGVLLAFASYNKFNNNCYQD
  ALVTSVVNCMTSFVSGFVIFTVLGYMAEMRNEDVSEVAKDAGPSLLFITYAEAIANMPAS
  TFFAIIFFLMLITLGLDSTFAGLEGVITAVLDEFPHVWAKRRERFVLAVVITCFFGSLVT
  LTFGGAYVVKLLEEYATGPAVLTVALIEAVAVSWFYGITQFCRDVKEMLGFSPGWFWRIC
  WVAISPLFLLFIICSFLMSPPQLRLFQYNYPYWSIILGYCIGTSSFICIPTYIAYRLIIT
  PGTFKERIIKSITPETPTEIPCGDIRLNAV
• Function: Serotonin transporter that cotransports serotonin with one Na(+) ion in exchange for one K(+) ion and possibly one proton in an overall electroneutral transport cycle. Transports serotonin across the plasma membrane from the extracellular compartment to the cytosol thus limiting serotonin intercellular signaling. Essential for serotonin homeostasis in the central nervous system. In the developing somatosensory cortex, acts in glutamatergic neurons to control serotonin uptake and its trophic functions accounting for proper spatial organization of cortical neurons and elaboration of sensory circuits. In the mature cortex, acts primarily in brainstem raphe neurons to mediate serotonin uptake from the synaptic cleft back into the pre-synaptic terminal thus terminating serotonin signaling at the synapse. Modulates mucosal serotonin levels in the gastrointestinal tract through uptake and clearance of serotonin in enterocytes. Required for enteric neurogenesis and gastrointestinal reflexes. Regulates blood serotonin levels by ensuring rapid high affinity uptake of serotonin from plasma to platelets, where it is further stored in dense granules via vesicular monoamine transporters and then released upon stimulation. Mechanistically, the transport cycle starts with an outward-open conformation having Na1(+) and Cl(-) sites occupied. The binding of a second extracellular Na2(+) ion and serotonin substrate leads to structural changes to outward-occluded to inward-occluded to inward-open, where the Na2(+) ion and serotonin are released into the cytosol. Binding of intracellular K(+) ion induces conformational transitions to inward-occluded to outward-open and completes the cycle by releasing K(+) possibly together with a proton bound to Asp-98 into the extracellular compartment. Na1(+) and Cl(-) ions remain bound throughout the transport cycle. Additionally, displays serotonin-induced channel-like conductance for monovalent cations, mainly Na(+) ions. The channel activity is uncoupled from the transport cycle and may contribute to the membrane resting potential or excitability.
• Tissue Specificity: Expressed in platelets (at protein level).
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  Serotonergic sy.pse (hsa04726)
• Reactome Pathway: Serotonin clearance from the synaptic cleft (R-HSA-380615)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Disputed	Autosomal dominant	[1]

This DOT Affected the Drug Response of 10 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	Sodium-dependent serotonin transporter (SLC6A4) affects the response to substance of Clozapine.	[20]
Haloperidol	DM96SE0	Approved	Sodium-dependent serotonin transporter (SLC6A4) increases the Tardive dyskinesia ADR of Haloperidol.	[21]
Fluoxetine	DM3PD2C	Approved	Sodium-dependent serotonin transporter (SLC6A4) decreases the response to substance of Fluoxetine.	[22]
Sertraline	DM0FB1J	Approved	Sodium-dependent serotonin transporter (SLC6A4) increases the response to substance of Sertraline.	[23]
Clomipramine	DMINRKW	Approved	Sodium-dependent serotonin transporter (SLC6A4) increases the Therapeutic agent toxicity ADR of Clomipramine.	[21]
Citalopram	DM2G9AE	Approved	Sodium-dependent serotonin transporter (SLC6A4) affects the response to substance of Citalopram.	[24]
Bupropion	DM5PCS7	Approved	Sodium-dependent serotonin transporter (SLC6A4) affects the response to substance of Bupropion.	[25]
Nortriptyline	DM4KDYJ	Approved	Sodium-dependent serotonin transporter (SLC6A4) decreases the response to substance of Nortriptyline.	[22]
Dextroamphetamine	DMMIHVP	Approved	Sodium-dependent serotonin transporter (SLC6A4) affects the response to substance of Dextroamphetamine.	[26]
Escitalopram	DMFK9HG	Approved	Sodium-dependent serotonin transporter (SLC6A4) increases the Dose-limiting toxicity ADR of Escitalopram.	[27]

25 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sodium-dependent serotonin transporter (SLC6A4).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[7]
Cocaine	DMSOX7I	Approved	Cocaine decreases the activity of Sodium-dependent serotonin transporter (SLC6A4).	[8]
Simvastatin	DM30SGU	Approved	Simvastatin increases the activity of Sodium-dependent serotonin transporter (SLC6A4).	[9]
Methamphetamine	DMPM4SK	Approved	Methamphetamine decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[10]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[2]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[2]
Lamivudine	DMI347A	Approved	Lamivudine increases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[11]
Gabapentin	DM6T924	Approved	Gabapentin decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[2]
Paroxetine	DM5PVQE	Approved	Paroxetine decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[12]
Sulfadiazine	DMTW3R8	Approved	Sulfadiazine decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[2]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[15]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin increases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[2]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[2]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[2]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Sodium-dependent serotonin transporter (SLC6A4).	[2]
Serotonin	DMOFCRY	Investigative	Serotonin increases the activity of Sodium-dependent serotonin transporter (SLC6A4).	[18]
Methylenedioxymethamphetamine	DMYVU47	Investigative	Methylenedioxymethamphetamine decreases the activity of Sodium-dependent serotonin transporter (SLC6A4).	[19]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Aripiprazole	DM3NUMH	Approved	Aripiprazole affects the binding of Sodium-dependent serotonin transporter (SLC6A4).	[13]
Mepyramine	DMB4SFH	Approved	Mepyramine affects the binding of Sodium-dependent serotonin transporter (SLC6A4).	[14]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium-dependent serotonin transporter (SLC6A4).	[16]

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