ArticleProceedings of the National Academy of Sciences of the United States of America2013
Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 87 citations in OpenAlex.
- The Role of Cholesterol at the CHOL2 Site and the Dimeric Interface in the Regulation of Serotonin Transporter Function and Dimerization.Biomolecules · 2026Article
- Cell membrane cholesterol affects serotonin transporter efflux due to altered transporter oligomerization.Molecular psychiatry · 2026Article
- Kappa opioid receptor antagonism restores phosphorylation, trafficking and behavior induced by a disease-associated dopamine transporter variant.Molecular psychiatry · 2025Article
- Absence of TAAR1 function increases methamphetamine-induced excitability of dorsal raphe serotonin neurons and drives binge-level methamphetamine intake.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Pathogenic variants at the N-terminal arginine residue 44 disrupt human GABA transporter 1 function: insights fromFrontiers in pharmacology · 2025Article
- Parkinson's disease gene, Synaptojanin1, dysregulates the surface maintenance of the dopamine transporter.NPJ Parkinson's disease · 2024Article
- Doxycycline reversal of amphetamine-induced mania-like behavior is related to adjusting brain monoamine abnormalities and antioxidant effects in primary hippocampal neurons.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
- Effects of SRI-32743, a Novel Quinazoline Structure-Based Compound, on HIV-1 Tat and Cocaine Interaction with Norepinephrine Transporter.International journal of molecular sciences · 2024Article
- PIPNature communications · 2024Article
- Article
- A Conserved Intramolecular Ion-Pair Plays a Critical but Divergent Role in Regulation of Dimerization and Transport Function among the Monoamine Transporters.International journal of molecular sciences · 2024Article
- Serotonin Signaling through Lipid Membranes.ACS chemical neuroscience · 2024Review
- Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors.Nature communications · 2024Article
- Bidirectional Allosteric Coupling between PIPInternational journal of molecular sciences · 2024Article
- Oligomerization of Monoamine Transporters.Sub-cellular biochemistry · 2024Review
- Electrostatic switch mechanisms of membrane protein trafficking and regulation.Biophysical reviews · 2023Review
- Structural insights into the conformational changes of BTR1/SLC4A11 in complex with PIPNature communications · 2023Article
- Serum Levels of 8-Iso-Prostaglandin F2α and Raftlin in Patients with Generalized Anxiety Disorder.Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology · 2023Article
- Overview of the structure and function of the dopamine transporter and its protein interactions.Frontiers in physiology · 2023Review
- Phosphatidylinositol 4,5-bisphosphate (PIPCommunications biology · 2022Article
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Authors and funding
19 authors at 5 institutions in 3 countries.
Funding
Abstract
Nerve functions require phosphatidylinositol-4,5-bisphosphate (PIP2) that binds to ion channels, thereby controlling their gating. Channel properties are also attributed to serotonin transporters (SERTs); however, SERT regulation by PIP2 has not been reported. SERTs control neurotransmission by removing serotonin from the extracellular space. An increase in extracellular serotonin results from transporter-mediated efflux triggered by amphetamine-like psychostimulants. Herein, we altered the abundance of PIP2 by activating phospholipase-C (PLC), using a scavenging peptide, and inhibiting PIP2-synthesis. We tested the effects of the verified scarcity of PIP2 on amphetamine-triggered SERT functions in human cells. We observed an interaction between SERT and PIP2 in pull-down assays. On decreased PIP2 availability, amphetamine-evoked currents were markedly reduced compared with controls, as was amphetamine-induced efflux. Signaling downstream of PLC was excluded as a cause for these effects. A reduction of substrate efflux due to PLC activation was also found with recombinant noradrenaline transporters and in rat hippocampal slices. Transmitter uptake was not affected by PIP2 reduction. Moreover, SERT was revealed to have a positively charged binding site for PIP2. Mutation of the latter resulted in a loss of amphetamine-induced SERT-mediated efflux and currents, as well as a lack of PIP2-dependent effects. Substrate uptake and surface expression were comparable between mutant and WT SERTs. These findings demonstrate that PIP2 binding to monoamine transporters is a prerequisite for amphetamine actions without being a requirement for neurotransmitter uptake. These results open the way to target amphetamine-induced SERT-dependent actions independently of normal SERT function and thus to treat psychostimulant addiction.
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