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Anant Parekh, PhD
Professor of Physiology
University of Oxford

Mailing Address:
Parks Road
Sherrington Building

Research Interests

Current Research

Over the past five years, research in Dr. Parekh’s lab has focused on four main themes:

  • How are CRAC channels activated? What is the nature of the signal sent from the stores that causes the CRAC channels to open?
  • Which gene(s) encode the CRAC channel?
  • Mitochondria are central to the gating of CRAC channels under physiological conditions. What is the precise role of mitochondria?
  • Which downstream targets are activated by Ca2+ entry through CRAC channels?

To address these issues, the Lab uses a combination of patch clamp electrophysiology (to measure ion movement through CRAC channels directly), fluorescence imaging of cytoplasmic Ca2+ concentration, confocal microscopy, molecular biology, biochemistry and functional assays including electrical capacitance measurements to monitor exocytosis in single cells and enzyme immuno-assay for detecting secreted paracrine signals like leukotriene C4.

Calcium Signalling and Cell Function

Animal cells are often stimulated by a rise in intracellular calcium (Ca2+) concentration.  One major way to increase intracellular Ca2+ is through opening of Ca2+-selective channel pores in the cell surface.  A key Ca2+ channel pore is the store-operated channel which is necessary for stimulating a diverse array of cellular responses.  Abnormalities in store-operated channel function have been linked to a variety of human disorders including primary immuno-deficiencies, inflammation and possibly Alzheimer’s disease.  Understanding how store-operated channels work may therefore result in new therapies for treating these disorders.

An increase in cytoplasmic Ca2+ concentration is used as a key signalling messenger in virtually every cell through the phylogenetic tree, where it regulates a broad spectrum of kinetically distinct processes.  Intracellular Ca2+ is often considered a “life-giving” signal because it is essential both for sperm motility and the acrosome reaction and, in the form of periodic Ca2+ oscillations, for fertilization of the egg.  Ca2+ is also vital for sustaining the life of the organism.  Distinct spatial and temporal patterns of cytoplasmic Ca2+ increases drive processes as diverse as exocytosis, gene transcription and cell motility.  Having given life, Ca2+ can also take it away.  This dark side of the Ca2+ signal can be executed through apoptosis or the more destructive and less specific necrosis.

Eucaryotic cells can increase their cytoplasmic Ca2+ concentration in one of two ways: release from intracellular stores or Ca2+ influx into the cell.  The Ca2+ release phase is transient sometimes fully deactivating within a few tens of seconds.  However, many key processes require sustained increases in intracellular Ca2+ and this is accomplished through Ca2+ entry into the cell.

A variety of different Ca2+-permeable channels have been found to co-exist in the plasma membrane.  In electrically non-excitable cells, which include the cells of the immune system, endothelia, epithelia and glia, the major Ca2+ influx pathway is the store-operated one, in which emptying of the intracellular inositol trisphosphate (InsP3)-sensitive Ca2+ stores results in the opening of store-operated Ca2+ channels in the plasma membrane.  Although a family of store-operated channels is thought to exist, the best characterised and most widely distributed member is the Ca2+-release activated Ca2+ (CRAC) channel.

It has now been established that Ca2+ entry flowing through CRAC channels (called CRAC current or ICRAC) is essential for the normal functioning of non-excitable cells. Abnormalities in ICRAC have been linked to debilitating diseases like certain primary immuno-deficiencies, acute pancreatitis and possibly Alzheimer’s disease.  Therefore understanding the molecular mechanisms that control CRAC channels may lead to the design of novel therapeutic agents aimed at treating these human disorders.

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