Functional expression of calcium-permeable Canonical Transient Receptor Potential 4-containing channels promotes migration of medulloblastoma cells

Abstract

Aberrant intracellular Ca²⁺ signalling contributes to the formation and progression of a range of distinct pathologies including cancers. Rises in intracellular Ca²⁺ concentration occur in response to Ca²⁺ influx through plasma membrane channels and Ca²⁺ release from intracellular Ca²⁺ stores, which can be mobilised in response to activation of cell surface receptors. OGR1 (Ovarian cancer G protein coupled Receptor 1, aka GPR68) is a proton-sensing G_q-coupled receptor that is most highly expressed in cerebellum. Medulloblastoma (MB) is the most common paediatric brain tumour that arises from cerebellar precursor cells. We find that nine distinct human MB samples all express OGR1. In both normal granule cells and the transformed human cerebellar granule cell line DAOY, OGR1 promotes expression of the proton-potentiated member of the Canonical Transient Receptor Potential (TRPC) channel family, TRPC4. Consistent with a role for TRPC4 in MB, we find that all MB samples also express TRPC4. In DAOY cells, activation of TRPC4-containing channels resulted in large Ca²⁺ influx and enhanced migration, while in normal cerebellar granule (precursor) cells and MB cells not derived from granule precursors, only small levels of Ca²⁺ influx and no enhanced migration was observed. Our results suggest that OGR1-dependent increases in TRPC4 expression may favour formation of highly Ca²⁺-permeable TRPC4-containing channels that promote transformed granule cell migration. Increased motility of cancer cells is a prerequisite for cancer invasion and metastasis, and our findings may point towards a key role for TRPC4 in progression of certain types of MB.

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