The cellular actions of many neurotransmitters and hormones are dependent on receptor-activated increases in intracellular calcium concentrations ([Ca2+]i) in their target cells. Our research is concerned with the pathways involved in the generation and control of these [Ca2+]i signals in secretory and other "non-excitable" cells. Such signals involve the receptor-mediated generation of a series of inositol phosphates one of which, inositol 1,4,5-trisphosphate (InsP3), is known to be responsible for the transient release of Ca2+ from certain intracellular stores initiating the Ca2+ signal. However, sustained signals depend on a receptor-activated entry of Ca2+ from the extracellular medium. The major focus of our research concerns the precise relationships between this receptor-activated entry of Ca2+ across the plasma membrane, the generation of specific inositol phosphates, and the status of the agonist-sensitive intracellular Ca2+ stores - particularly during the pronounced [Ca2+]i oscillations that form the signals that are usually seen under physiological conditions. We have recently identified and described a novel Ca2+ entry pathway regulated by a phospholipase A2-mediated generation of arachidonic acid that appears to be specifically responsible for the control of Ca2+ entry under such conditions. The nature, and mechanism of activation, of this novel pathway is the major focus of our current research.
Techniques used include digital imaging, real-time confocal imaging, and photon-counting microfluorimetric measurements of intracellular Ca2+ concentrations in single cells; flash photolysis of intracellularly incorporated "caged" molecules; patch-clamp analysis of ion-channel activities; and biochemical and molecular studies of the generation and metabolism of inositol phosphates, arachidonic acid, and other intracellular signaling molecules. |
Shuttleworth, T.J., Thompson, J.L., and Mignen, O. (2004) ARC channels: A novel pathway for receptor-activated calcium entry. Physiology 19:355-361.
Sneyd, J., Tsaneva-Atanasova, K., Yule, D.I., Thompson, J.L., and Shuttleworth, T.J. (2004) Control of calcium oscillations by membrane fluxes. Proc. Natl. Acad. Sci. USA 101:1392-1396.
Melvin, J.E., Yule, D., Shuttleworth, T.J., and Begenisich, T. (2005) Regulation of fluid and electrolyte secretion in salivary gland acinar cells. Annu. Rev. Physiol. 67:445-469.
Mignen, O., Thompson, J.L., and Shuttleworth, T.J. (2005) Arachidonate-regulated Ca2+-selective (ARC) channel activity is modulated by phosphorylation and involves an A-kinase anchoring protein. J. Physiol.567.3:787-798.
Mignen, O., Thompson, J.L., Yule, D.I., and Shuttleworth, T.J. (2005) Agonist activation of arachidonate-regulated Ca2+-selective (ARC) channels in murine parotid and pancreatic acinar cells. J. Physiol. 564.3:791-801.
Mignen, O., Brink, C., Enfissi, A., Nadkarni, A., Shuttleworth, T.J., Giovannucci, D.R., and Capiod, T. (2005) Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells. J. Cell Sci. 118:5615-5623.
Mignen, O., Thompson, JL., and Shuttleworth, T.J. (2007) STIM1 regulates Ca2+ entry via arachidonate-regulated Ca2+-selective (ARC) channels without store depletion or translocation to the plasma membrane. J. Physiol. 579.3:703-715.
Wood, C.M., Munger, Thompson, J., and Shuttleworth, T.J. (2007) Control of rectal gland secretion by blood acid-base status in the intact dogfish shark (Squalus acanthias). Respir. Physiol. Neurobiol. 156:220-228.
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