Furthermore, phosphorylation of STX at S14 in the N-terminus segment, by casein kinase-2 (CK2), has been suggested to have dramatic effects on DAT/STX localization and subsequently on DAT synaptic transmission, all of which indicates that during cell signaling STX is engaged in regulated, functionally relevant interactions with DAT through its own N-terminus.
It is commonly believed that the reinforcing properties of cocaine depend upon interaction with the DAT, however, cocaine is still reinforcing in mice with a genetic deletion of the DAT (DAT-KO mice).
Because this action on dopaminergic markers is mediated by DAT, these results provide evidence that Mn interacts directly with DAT and are consistent with other studies that indicate an interaction of Mn with DAT (Anderson et al. 2007; Chen et al. 2006; Ingersoll et al. 1999).
The interaction of Dat with AcCoA had a higher affinity, with a Ka of 1.88×10 M−1.88×10
The ITC data revealed that the interaction of Dat with dopamine appeared to be an exothermic reaction with enthalpy (Δ H =−7.85 kcal/mol, and entropy (Δ S =−5.32 cal/mol per K. Fitting to one set of the site-binding model, the Ka of dopamine binding to Dat was calculated to be 3.88×10 M−1, and the binding constant Kd was 25.9 μM.
The loss of the Y3356.68 interaction with E4288.66 destabilizes S1-DAT and steers the transporter towards an inward-facing conformation.
Notably, the effect of Y3356.68 mutation to Ala was shown to be rescuable by the addition of Zn2+ rescues [61], and the mechanism explained by the ability of Zn2+ to replace the energetically favorable Y3356.68 interaction with R60 NT) thereby reinforcing S1-DAT, and restoring the equilibrium between S1-DAT and the inward-facing conformation that had been lost in the Y3356.68A mutant [16].
The reasons for such differences currently remain unknown and several hypotheses have been proposed, including L-DOPA-induced modification of DAT expression, interaction with radiotracers or accelerated loss of nigrostriatal terminals.
This bicyclic core structure constitutes a novel chemical scaffold in DAT inhibitor design, which may provide new insights into the 3D structure of the DAT and its interaction with cocaine and DA.
The putamen DAT concentration and its interaction with diagnosis were thus included as predictor terms when the putamen DAT concentration was not the dependent variable.
