The two-pore domain potassium channel TASK-1 plays an important role in various cell types including neurons, cardiac muscle and endocrine cells. To identify proteins interacting with TASK-1 we performed a split-ubiquitin based yeast two-hybrid screen with a brain cDNA library. One of the interacting proteins found in this way was the Secretory Carrier Membrane Protein-5 (SCAMP5). Expression of TASK-1 in Xenopus oocytes gave rise to an acid-sensitive outward current. The amplitude of this current was reduced to about 50% when TASK-1 was co-expressed with SCAMP5. A similar reduction of current amplitude was observed after co-expression of the channel with SCAMP1 and SCAMP2. An antibody-based luminometric assay showed that co-expression of SCAMPs substantially reduced surface expression of TASK-1. Systematic mutagenesis revealed that asparagine-proline-phenylalanine (NPF) domains in the amino terminus of SCAMP proteins are essential for the effects of SCAMPs on TASK-1. Direct association of SCAMPs with TASK-1 was further supported by co-localization experiments and GST pull down analysis using lysates from transfected HELA cells. Voltage clamp measurements carried out in Xenopus oocytes expressing both TASK-1 and one of the SCAMP proteins in the presence of Dynasore, a cell-permeable inhibitor of dynamin, virtually abolished the effect of SCAMPs on current amplitude. Nystatin, an inhibitor of the lipid raft-caveolae endocytosis did not alter the effect of SCAMPs on TASK-1 channels. Our experiments suggest that SCAMP proteins might play a role in the clathrin-mediated endocytosis of TASK-1 channels via NPF domains.