A network of phosphatidylinositol (4,5)-bisphosphate (PIP2) binding sites on the dopamine transporter regulates amphetamine behavior in Drosophila Melanogaster

Lipid fingerprints are similar between SLC6 transporters in the neuronal membrane

“…The enrichment of interactions with cationic amino acids is consistent with the PI lipids forming electrostatic interactions with the lipid headgroup. This has been previously reported to be important for stabilizing PI interactions with proteins [40]. In GlyT2, and PA (1 PAPA in the membrane), form few contacts with each transporter; DAG (1 PADG in each leaflet) has transient contacts with each transporter.…”

“…The interactions with alanine in GlyT2 occur in TM4 and with Ala190 in the N-terminus; in hSERT, the N-terminus and TM4 interactions involve tryptophan, glycine, lysine, valine, and isoleucine. In dDAT, the N-terminus and TM4 interactions are with arginine, tryptophan, phenylalanine, and serine.The binding of phosphatidylinositol (4,5)-bisphosphate to the N-terminus (Lys3 and Lys5) of hDAT has been shown to support dopamine release in response to amphetamine[40]. PI lipids form contacts with the N-terminus of all three transporters; however, these interactions do not exclusively occur with phosphatidylinositol bisphosphate lipids.…”

Direct dopamine terminal regulation by local striatal microcircuitry

“…DAT is a target of many psychotropic drugs such as cocaine, methamphetamine, and amphetamine (Baumann et al., 2012; Belovich et al., 2019; Cartier et al., 2015; Hamilton et al., 2014; Rothman et al., 2001) and therefore has been well‐studied for its role in substance use disorder, motivation, and dopamine signaling. Impaired clearance, resulting from inhibition of DAT by compounds such as cocaine, produces elevated levels of dopamine in the extracellular space for prolonged periods of time, and consequently increases postsynaptic dopamine receptor activation on target cells.…”

“…The N and C termini of DAT can both be post‐translationally modified to alter its membrane stability and function (Belovich et al., 2019; Cartier et al., 2015; Hamilton et al., 2014; Sweeney, Tremblay, Stockner, Sitte, & Melikian, 2017). Protein kinase C (PKC) has been shown to phosphorylate the DAT, cause internalization, and decrease transport kinetics (Foster, Adkins, Lever, & Vaughan, 2008; Loder & Melikian, 2003; Moritz et al., 2015).…”

“…DAT is a target of many psychotropic drugs such as cocaine, methamphetamine, and amphetamine (Baumann et al, 2012;Belovich et al, 2019;Cartier et al, 2015;Hamilton et al, 2014;Rothman et al, 2001) and therefore has been well-studied for its role in substance use disorder, motivation, and dopamine signaling. half-life of dopamine in the extracellular space.…”