Extracellular acidification elicits spatially and temporally distinct Ca2+ signals.
Extracellular acidification accompanies neoplastic transformation of tissues and increases with tumor aggressiveness [1, 2]. The intracellular signaling cascade triggered by this process remains poorly understood and may be linked to recently discovered proton-activated G protein-coupled receptors such as OGR1 and G2A [3, 4]. Here, we report that OGR1 and G2A are expressed in human medulloblastoma tissue and its corresponding neuronal cell line. We show that extracellular acidification activates phospholipase C, IP(3) formation, and subsequent Ca2+ release from thapsigargin-sensitive stores in neurons. The number of responsive cells and the amount of Ca2+ released from stores correlated positively with the extent of extracellular acidification. Ca2+ release recruited the MEK/ERK pathway, providing a mechanistic explanation for how acidification stimulates cell growth. In addition, acidification activated Ca2+-permeable ion channels through a mechanism dependent on phospholipase C but independent of store depletion or a cytoplasmic Ca2+ rise. Hence, extracellular acidification, to levels seen in tumor tissue, activates temporally and spatially distinct pathways that elevate Ca2+ and may be directly relevant for tumor cell biology.
Huang
Wan-Chen
WC
Department of Physiology, Anatomy, and Genetics, Sherrington Building, Oxford University, Parks Road, Oxford OX1 3PT, United Kingdom.
Swietach
Pawel
P
Proton Transport Group, Sherrington Building, Oxford University, Parks Road, Oxford OX1 3PT, United Kingdom.
Vaughan-Jones
Richard D
RD
Proton Transport Group, Sherrington Building, Oxford University, Parks Road, Oxford OX1 3PT, United Kingdom.
Ansorge
Olaf
O
Department of Neuropathology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, United Kingdom.
Glitsch
Maike D
MD
Department of Physiology, Anatomy, and Genetics, Sherrington Building, Oxford University, Parks Road, Oxford OX1 3PT, United Kingdom. Electronic address: maike.glitsch@dpag.ox.ac.uk.
D020013:Calcium Signaling / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008527:Medulloblastoma / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
D018797:Cell Cycle Proteins; C115270:G2A receptor; C486281:GPR68 protein, human; D043562:Receptors, G-Protein-Coupled; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases