Adenosine diphosphate inhibits the serotonin transporter.
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.
Anderson
G M
GM
Child Study Center, Yale University School of Medicine, New Haven, CT 06520-7900, USA.
Hall
L M
LM
Horne
W C
WC
Yang
J X
JX
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015283:Citalopram / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D014316:Tritium
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D015283:Citalopram; D014316:Tritium; D012701:Serotonin; D000001:Calcimycin; D000244:Adenosine Diphosphate; D011493:Protein Kinase C; D004837:Epinephrine