Wnt ligands are a diverse family of secreted polypeptides, implicated in multiple pathways during development and in disease. Nineteen Wnt ligands are known in humans and activation of Wnt binding receptors leads nuclear translocation of ß-catenin downstream. Application of subset of Wnts activate a Ca2+ signal in prostate, breast and bowel cancer cells lines (Thrasivoulou et al, 2013). To investigate early events in this signalling pathway we have used high throughput techniques (Qpatch) as well as single cell tight seal patch recording with [Ca2+]i imaging to show that an early step in the Wnt signal cascade is the control of membrane potential. Using PC3 prostate cancer cell lines, a local application via a puff pipette of either Wnts 5A, 9B or 10B produced an small initial depolarisation, followed by a hyperpolarization of up to 30 mV. Simultaneous recording of Ca2+ with OGB5N (Kd = 20 µM) showed a parallel biphasic response, with an early Ca2+ decrease. Determination of the Wnt concentration using a dye in the delivery pipette indicated a threshold response occurs for Wnt concentrations in the low nM range with a response latency less than 200 ms. High-throughput measurements, using controlled microfluidics, also consistently showed an early (<3s) current response at levels down to 2 nM. As in earlier Ca2+ imaging experiments, a bolus delivering higher sustained concentrations to the bath produced a larger but delayed (100-200s) Ca2+ rise. Associated with this rise was a large cationic current reversing around +10mV, which sometimes though not always was reversible. This current was often accompanied by damped Ca2+ and membrane current oscillations (rate 0.07-0.05 Hz). The phenomena are simply explained by activation of a store operated calcium release. The net effect ensures Wnt activation leads to Ca2+ entry by a voltage-independent non-selective pathway and a release of [Ca2+]i. We suggest that Wnt control of membrane potential is a signal amplifying mechanism for low nanomolar levels of Wnt, and further suggests that modulation of this critical cell signal transduction pathway may be a means to control cell proliferation for some cancers.