Wnts control membrane potential in mammalian cancer cells

Key points Wnt ligands belonging to both canonical and non-canonical Wnt pathways regulate membrane potential signifying a very early event in the signal transduction. Wnts activate K+ currents by elevating intracellular Ca2+ and trigger Ca2+ release from intracellular stores. Control of potential by Wnt ligands has significant implications for gene transcription and opens up a novel avenue to interfere with this critical pathway. The Wnt signalling network determines gene transcription with free intracellular Ca2+ ( Ca i2+) and beta-catenin as major intracellular signal transducers. Despite its critical importance during development and disease, many of the basic mechanisms of Wnt signal activation remain unclear. Here we show by single cell recording and simultaneous Ca i2+ imaging in mammalian prostate cancer cells that an early step in the signal cascade is direct action on the cell membrane potential. We show that Wnt ligands 5A, 9B and 10B rapidly hyperpolarized the cells by activating K+ current by Ca2+ release from intracellular stores. Medium-throughput multi-well recordings showed responses to Wnts at concentrations of 2 nm. We identify a putative target for early events as a TRPM channel. Wnts thus act as ligands for ion channel activation in mammalian cells and membrane potential is an early indicator of control of transcription.