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Proton dependence of intracellular calcium signalling in the cerebellum in health and disease - role of extracellular pH sensing receptors and ion channels.

TRPC6 expression in rat cerebellum
TRPC6 expression in rat cerebellum

My group is interested in how the physical and (bio)chemical environment influence cells and their interactions with each other in the mammalian brain. We are particularly interested in proton-mediated mechanisms and mechanical cues, and how these come together to shape cell development, physiology and pathology.

Our protein of interest is OGR1 (aka GPR68), one of only three extracellular proton-sensing G protein coupled receptors that acts as an extracellular pH sensor in a variety of tissues and is the only Gq-coupled proton sensor. Hence, it can translate increases in extracellular proton concentration (i.e. decreases in extracellular pH) into increases in intracellular Ca2+ concentration. Changes in intracellular Ca2+ concentration can give rise to a plethora of different effects, including synthesis and release of biologically active chemicals (e.g. hormones, neurotransmitters), changes in motility, and gene transcription, and hence influences processes including differentiation, proliferation and cell death. We have recently shown that OGR1 is not only a proton-sensor but also a mechano-sensor: Membrane stretch-mediated actin polymerisation is an absolute requirement for OGR1 function, and hence this receptor should be considered a coincidence detector for both extracellular protons and membrane stretch. It makes OGR1 a unique cell surface receptor that integrates chemical (protons) and physical (membrane-stretch) cues.

Changes in tissue stiffness accompany and shape development. Crucially, there are stiffness differences within as well as between brain cells, and across brain regions, and all these mechanical cues are important for proper development and signalling. Most if not all pathologies are accompanied by acidification of the interstitial tissue fluid and increased stiffness of the extracellular matrix, and cells exhibit dysregulated intracellular Ca2+ signals under pathological conditions. Since OGR1 is a coincidence detector for stretch-induced actin polymerisation and extracellular acidification, and it can link to increases in intracellular Ca2+ concentration, it makes an attractive target when investigating how pathologies develop and progress. We are interested in OGR1 in the context of normal brain development, brain cancers (of the cerebellum, called medulloblastomas) and ischaemic stroke.

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