Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we will assume that you are happy to receive all cookies and you will not see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Our team

  • Maike Glitsch
    Maike Glitsch

    Associate Professor of Biomedical Science

  • Claire Pearson
    Claire Pearson

    Oxion Student

Related research themes

We study everything from the structure of ion channels and transporters right up to their role in behaviour and human disease.
Cell Physiology

We study everything from the structure of ion ...

We host a number of internationally recognised neuroscience groups, with expertise in a wide range of experimental and computational methods.

We host a number of internationally recognised ...

We dissect the molecular and cellular mechanisms underlying a range of developmental and reproductive processes.
Development & Cell Biology

We dissect the molecular and cellular mechanisms ...

We use the full range of modern molecular genetic and imaging techniques to study a range of metabolic areas.
Metabolism & Endocrinology

We use the full range of modern molecular genetic ...