Polyphosphate (polyP) is an inorganic polymer built of tens to hundreds of
phosphates, linked by high-energy phosphoanhydride bonds. PolyP forms
complexes and modulates activities of many proteins including ion channels.
Here we investigated the role of polyP in the function of the transient receptor
potential melastatin 8 (TRPM8) channel. Using whole-cell patch-clamp
and fluorescent calcium measurements we demonstrate that enzymatic breakdown
of polyP by exopolyphosphatase (scPPX1) inhibits channel activity in
human embryonic kidney and F-11 neuronal cells expressing TRPM8. We
demonstrate that the TRPM8 channel protein is associated with polyP. Furthermore,
addition of scPPX1 altered the voltage-dependence and blocked the
activity of the purified TRPM8 channels reconstituted into planar lipid bilayers,
where the activity of the channel was initiated by cold and menthol
in the presence of phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2). The