Wnts control membrane potential in mammalian cancer cells

TY - JOUR

T1 - Wnts control membrane potential in mammalian cancer cells

AU - Ashmore, Jonathan

AU - Olsen, Hervør

AU - Sørensen, Naja

AU - Thrasivoulou, Christopher

AU - Ahmed, Aamir

PY - 2019/12/15

Y1 - 2019/12/15

N2 - 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 Ca 2+ and trigger Ca 2+ 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. Abstract: The Wnt signalling network determines gene transcription with free intracellular Ca 2+ (Ca 2+ i) and β-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 2+ i 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 Ca 2+ 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.

AB - 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 Ca 2+ and trigger Ca 2+ 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. Abstract: The Wnt signalling network determines gene transcription with free intracellular Ca 2+ (Ca 2+ i) and β-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 2+ i 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 Ca 2+ 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.

KW - WNT

KW - membrane potential

KW - CANCER

U2 - 10.1113/JP278661

DO - 10.1113/JP278661

M3 - Article

SN - 0022-3751

VL - 597

SP - 5899

EP - 5914

JO - The Journal of Physiology

JF - The Journal of Physiology

IS - 24

ER -