Adenosine diphosphate inhibits the serotonin transporter.

ABSTRACT

Adenosine 5'-diphosphate (ADP) caused rapid and significant reductions in the rates of [3H]serotonin uptake observed for human platelets, human platelet vesicles, and rat brain synaptic vesicles. Estimated Vmax values in platelets (N = 15). platelet vesicles (N = 3), and synaptic vesicles (N = 3) exposed to 100 microM ADP were 42.3 +/- 11.4%, 78.8 +/- 1.4%, and 56.8 +/- 9.9% of control values, respectively. The EC50 values observed for ADP in platelets and platelet vesicles were 10-24 microM. Exposure to 100 microM ADP had small, inconsistent effects on KM values observed for the platelet transporter. ADP (100 microM) caused only a slight competitive inhibition of the platelet membrane binding of [3H]citalopram, a ligand for the 5HT uptake site of the transporter (5.0% displacement of 1.0 nM [3H]citalopram, 13% increase in apparent KD). The ADP analogue 2-methylthioADP caused similar decreases in the rates of platelet [3H]serotonin uptake, while a number of other related compounds had little or no effect on rates of platelet uptake. The ADP-effect on uptake was rapid, occurring in less than 2.5 s. and was additive with reductions produced by protein kinase C (PKC) activation. The ADP-induced decreases in uptake did not appear to occur through the ADP receptor or known platelet second messenger systems. The exact mechanism of the ADP-effect and its functional significance remain to be determined.