SLC6A4

SLC6A4/SERT is a sodium- and chloride-dependent serotonin reuptake transporter (507 amino acids, 57 kDa). It functions by coupling the transmembrane import of serotonin (5-hydroxytryptamine) to the co-transport of one Na+ and one Cl- ion, with counter-transport of K+, down the electrochemical gradient. The protein contains the SNF domain (Pfam PF00209), with predicted Na+ binding sites at residues 214, 246, 311, and 314 (corresponding to the Na1 and Na2 sites characterized in LeuT and human SERT crystal structures), and a conserved extracellular disulfide bond (C77-C86). MDMA binds in the central substrate-binding site (S1 site) within the transmembrane domain, overlapping with the serotonin binding pocket; conservation of key residues at this site in octopus SERT provides the structural basis for MDMA's cross-species pharmacological activity. It belongs to PANTHER subfamily PTHR11616:SF279 (sodium-dependent serotonin transporter) and appears to be present as a single copy in the O. bimaculoides genome, consistent with the ancestral state for monoamine transporters [PMID:26268193]. Cross-species chimera studies between human and Drosophila SERT have mapped the structural determinants of transport specificity within this conserved protein family [PMID:9779469].

• PMID:30245101
  the evolutionary conservation of the serotonin transporter (SERT, encoded by the Slc6A4 gene) binding site of MDMA in the O. bimaculoides genome
• PMID:30245101
  the SERT transmembrane domain binding pocket for MDMA shows conservation of key residues across vertebrate and invertebrate species

SERT mediates serotonin reuptake at the synapse, clearing released serotonin from the synaptic cleft into the presynaptic neuron. This is the primary mechanism for terminating serotonergic neurotransmission in both vertebrate and invertebrate nervous systems. In the octopus brain, serotonin modulates both short-term and long-term synaptic plasticity at the median superior frontal lobe (MSFL)-to-amacrine (AM) synapse in the vertical lobe, the primary learning and memory center [PMID:35107842]. Serotonergic neurotransmission is also critical for regulating social behavior [PMID:30245101]. Furthermore, antidepressants targeting the serotonergic system (SSRIs such as fluoxetine, SNRIs such as venlafaxine) alter innate burying/camouflage behavior in juvenile cuttlefish at environmentally relevant concentrations, demonstrating the broad importance of serotonin signaling in cephalopod behavior [PMID:31610357]. By controlling the duration and magnitude of serotonin signaling at the synapse, SERT plays a key role in modulating serotonin-dependent neural circuits.

• PMID:30245101
  the neural mechanisms subserving social behaviors exist in O. bimaculoides and indicate that the role of serotonergic neurotransmission in regulating social behaviors is evolutionarily conserved
• PMID:35107842
  5-HT, octopamine, dopamine and nitric oxide modulate short- and long-term VL synaptic plasticity
• PMID:31610357
  Both compounds act on the serotoninergic system, which may result in behavioural impairment, especially in juvenile animals presumed to be more susceptible to low concentrations than adults.

SERT-mediated serotonergic neurotransmission regulates social behavior in O. bimaculoides. Edsinger and Dolen (2018) showed that MDMA, which binds SERT at the central S1 binding site and reverses serotonin transport (increasing extracellular serotonin), induces prosocial behavior in this normally asocial and solitary octopus species. Using a three- chambered social approach task (with one chamber containing a novel conspecific in a perforated container), MDMA-treated octopuses spent significantly more time in the social proximity zone and exhibited extensive ventral-surface tactile exploration of conspecifics, a behavior not seen in saline controls. The effects were dose-dependent, observed after bath application of MDMA at doses comparable to those used in rodent studies. This is particularly remarkable because octopus and human lineages diverged over 500 million years ago and cephalopods have a fundamentally different brain organization (distributed nervous system with 2/3 of neurons in the arms), yet the serotonergic social circuitry is maintained even in species that rarely deploy it [PMID:30245101].

• PMID:30245101
  MDMA enhances acute prosocial behaviors in Octopus bimaculoides, an otherwise asocial and solitary species
• PMID:30245101
  the role of serotonergic neurotransmission in regulating social behaviors is evolutionarily conserved
• PMID:30245101
  the neural mechanisms subserving social behaviors exist in O. bimaculoides and indicate that the role of serotonergic neurotransmission in regulating social behaviors is evolutionarily conserved