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Trevor Shuttleworth

TitleProfessor
InstitutionSchool of Medicine and Dentistry
DepartmentPharmacology and Physiology
AddressUniversity of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 711
Rochester NY 14642
Other Positions
TitleProfessor
InstitutionUniversity of Rochester Medical Center
DepartmentCenter for Oral Biology

 
 Awards And Honors
1969 - 1972University of Otago Teaching Fellowship, University of Otago, New Zealand
1972 - 1974Science Research Council Fellowship (U.K.), University of Lancaster, England
1979     Session Chair - Society for Experimental Biology Conference, Lancaster, U.K.
1981     Session Chair - Seminar Series Symposium of the Society for Experimental Biology, Durham, U.K.
1984     Session Chair - Society for Experimental Biology Conference, Cardiff, U.K.
1985     Session Chair - Society for Experimental Biology Conference, Bangor, U.K.
1986     Session Chair - IUPS International Congress, Vancouver, Canada
1986     Session Chair - IUPS Satellite Symposium on "Membrane Transport and Control: Comparative Mechanisms", Banff, Canada
1987     Session Chair - Society for Experimental Biology Conference, York, U.K.
1990     Session Chair - International Symposium on "Mechanisms of Systemic Regulation in Lower Vertebrates", Göttingen, Germany
1992     Session Chair - Joint Meeting of the APS, ASZ, CSZ and SEB, Cambridge, England
1993     Session Chair - Experimental Biology 1993 (FASEB) meeting, New Orleans
2000     Session Chair - International Workshop on "Experimental and Theoretical Calcium Dynamics" Max-Planck institute for the Physics of Complex Systems, Dresden, Germany
2003     Session Chair - Salivary Glands and Saliva  | Gordon Research Conference
2003     Session Chair - 5th UK Calcium Signalling Conference, Liverpool, England.
2003     Session Chair - Professor Sir Michael Berridge Retirement Conference, Cambridge, England.
2011     Plenary Speaker, Ion Channel Signaling Mechanisms: from Basic Science to Clinical Applications
2012     Chair and Organizer, Satellite Symposium on "Orai Channels--New Insights, New Ideas"  | 56th Annual Biophysical Society Meeting
 
 Overview
The cellular actions of many neurotransmitters and hormones are dependent on receptor-activated increases in intracellular calcium concentrations in their target cells. In various secretory and other "non-excitable" cells, the physiologically relevant signals often take the form of a series of Ca2+ oscillations, and many critical cellular responses are tuned to respond to the specific frequency of such oscillations. A key factor in sustaining these signals and determining their frequency, is the receptor-activated entry of Ca2+ from the extracellular medium. Our research concerns the nature of the conductances responsible for this entry, and their specific roles in modulating the overall Ca2+ signal. Specifically, our recent research has focused on the ARC channel – a novel Ca2+ entry channel that is activated by the receptor-mediated generation of arachidonic acid, and which we first described a few years ago. Importantly, it is this channel that appears to play the major role in the entry of Ca2+ during the generation of the oscillatory Ca2+ signals in several cell types. We have recently characterized the key molecular components of this channel, revealing that it is a member of a new family of channels – the "Orai-based channels". This molecular characterization has opened up new opportunities for the analysis of its nature, mechanism of activation, and regulation. This, along with identifying how the Ca2+ entering via this channel acts to modulate the frequency of the agonist-induced Ca2+ oscillations, forms the major focus of our current research.

Techniques used include patch-clamp analysis of ion-channel activity, digital imaging, real-time confocal imaging, and photon-counting microfluorimetric measurements of intracellular Ca2+ concentrations in single cells, and biochemical and molecular studies of the proteins that form the channel and its regulators.

 
 Selected Publications
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  1. Thompson JL, Shuttleworth TJ. Exploring the unique features of the ARC channel, a store-independent Orai channel. Channels (Austin). 2013 Sep-Oct; 7(5):364-73.
    View in: PubMed
  2. Thompson JL, Shuttleworth TJ. How Many Orai's Does It Take to Make a CRAC Channel? Sci Rep. 2013 Jun 7; 3:1961.
    View in: PubMed
  3. Thompson JL, Shuttleworth TJ. Molecular basis of activation of the arachidonate-regulated Ca2+ (ARC) channel, a store-independent Orai channel, by plasma membrane STIM1. J Physiol. 2013 Jul 15; 591(Pt 14):3507-23.
    View in: PubMed
  4. Thompson JL, Mignen O, Shuttleworth TJ. The ARC Channel-An Endogenous Store-Independent Orai Channel. Curr Top Membr. 2013; 71:125-48.
    View in: PubMed
  5. Shuttleworth TJ. Orai channels - new insights, new ideas. J Physiol. 2012 Sep 1; 590(Pt 17):4155-6.
    View in: PubMed
  6. Thompson JL, Shuttleworth TJ. A plasma membrane-targeted cytosolic domain of STIM1 selectively activates ARC channels, an arachidonate-regulated store-independent Orai channel. Channels (Austin). 2012 Sep 1; 6(5):370-8.
    View in: PubMed
  7. Palk L, Sneyd J, Patterson K, Shuttleworth TJ, Yule DI, Maclaren O, Crampin EJ. Modelling the effects of calcium waves and oscillations on saliva secretion. J Theor Biol. 2012 Jul 21; 305:45-53.
    View in: PubMed
  8. Shuttleworth TJ. STIM and Orai proteins and the non-capacitative ARC channels. Front Biosci. 2012; 17:847-60.
    View in: PubMed
  9. Shuttleworth TJ. Orai3--the 'exceptional' Orai? J Physiol. 2012 Jan 15; 590(Pt 2):241-57.
    View in: PubMed
  10. Thompson JL, Shuttleworth TJ. Orai channel-dependent activation of phospholipase C-d: a novel mechanism for the effects of calcium entry on calcium oscillations. J Physiol. 2011 Nov 1; 589(Pt 21):5057-69.
    View in: PubMed
  11. Thompson J, Mignen O, Shuttleworth TJ. The N-terminal domain of Orai3 determines selectivity for activation of the store-independent ARC channel by arachidonic acid. Channels (Austin). 2010 Sep-Oct; 4(5):398-410.
    View in: PubMed
  12. Palk L, Sneyd J, Shuttleworth TJ, Yule DI, Crampin EJ. A dynamic model of saliva secretion. J Theor Biol. 2010 Oct 21; 266(4):625-40.
    View in: PubMed
  13. Mignen O, Thompson JL, Shuttleworth TJ. The molecular architecture of the arachidonate-regulated Ca2+-selective ARC channel is a pentameric assembly of Orai1 and Orai3 subunits. J Physiol. 2009 Sep 1; 587(Pt 17):4181-97.
    View in: PubMed
  14. Shuttleworth TJ. Arachidonic acid, ARC channels, and Orai proteins. Cell Calcium. 2009 Jun; 45(6):602-10.
    View in: PubMed
  15. Thompson JL, Mignen O, Shuttleworth TJ. The Orai1 severe combined immune deficiency mutation and calcium release-activated Ca2+ channel function in the heterozygous condition. J Biol Chem. 2009 Mar 13; 284(11):6620-6.
    View in: PubMed
  16. Mignen O, Thompson JL, Shuttleworth TJ. Orai1 subunit stoichiometry of the mammalian CRAC channel pore. J Physiol. 2008 Jan 15; 586(2):419-25.
    View in: PubMed
  17. Mignen O, Thompson JL, Shuttleworth TJ. Both Orai1 and Orai3 are essential components of the arachidonate-regulated Ca2+-selective (ARC) channels. J Physiol. 2008 Jan 1; 586(1):185-95.
    View in: PubMed
  18. Gin E, Crampin EJ, Brown DA, Shuttleworth TJ, Yule DI, Sneyd J. A mathematical model of fluid secretion from a parotid acinar cell. J Theor Biol. 2007 Sep 7; 248(1):64-80.
    View in: PubMed
  19. Shuttleworth TJ, Thompson JL, Mignen O. STIM1 and the noncapacitative ARC channels. Cell Calcium. 2007 Aug; 42(2):183-91.
    View in: PubMed
  20. Mignen O, Thompson JL, Shuttleworth TJ. STIM1 regulates Ca2+ entry via arachidonate-regulated Ca2+-selective (ARC) channels without store depletion or translocation to the plasma membrane. J Physiol. 2007 Mar 15; 579(Pt 3):703-15.
    View in: PubMed
  21. Shuttleworth TJ, Thompson J, Munger RS, Wood CM. A critical analysis of carbonic anhydrase function, respiratory gas exchange, and the acid-base control of secretion in the rectal gland of Squalus acanthias. J Exp Biol. 2006 Dec; 209(Pt 23):4701-16.
    View in: PubMed
  22. Wood CM, Munger RS, Thompson J, Shuttleworth TJ. Control of rectal gland secretion by blood acid-base status in the intact dogfish shark (Squalus acanthias). Respir Physiol Neurobiol. 2007 May 14; 156(2):220-8.
    View in: PubMed
  23. Mignen O, Brink C, Enfissi A, Nadkarni A, Shuttleworth TJ, Giovannucci DR, Capiod T. Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells. J Cell Sci. 2005 Dec 1; 118(Pt 23):5615-23.
    View in: PubMed
  24. Mignen O, Thompson JL, Shuttleworth TJ. Arachidonate-regulated Ca2+-selective (ARC) channel activity is modulated by phosphorylation and involves an A-kinase anchoring protein. J Physiol. 2005 Sep 15; 567(Pt 3):787-98.
    View in: PubMed
  25. Mignen O, Thompson JL, Yule DI, Shuttleworth TJ. Agonist activation of arachidonate-regulated Ca2+-selective (ARC) channels in murine parotid and pancreatic acinar cells. J Physiol. 2005 May 1; 564(Pt 3):791-801.
    View in: PubMed
  26. Melvin JE, Yule D, Shuttleworth T, Begenisich T. Regulation of fluid and electrolyte secretion in salivary gland acinar cells. Annu Rev Physiol. 2005; 67:445-69.
    View in: PubMed
  27. Shuttleworth TJ, Thompson JL, Mignen O. ARC channels: a novel pathway for receptor-activated calcium entry. Physiology (Bethesda). 2004 Dec; 19:355-61.
    View in: PubMed
  28. Shuttleworth TJ. Receptor-activated calcium entry channels--who does what, and when? Sci STKE. 2004 Jul 27; 2004(243):pe40.
    View in: PubMed
  29. Sneyd J, Tsaneva-Atanasova K, Yule DI, Thompson JL, Shuttleworth TJ. Control of calcium oscillations by membrane fluxes. Proc Natl Acad Sci U S A. 2004 Feb 3; 101(5):1392-6.
    View in: PubMed
  30. Bruce JI, Giovannucci DR, Blinder G, Shuttleworth TJ, Yule DI. Modulation of [Ca2+]i signaling dynamics and metabolism by perinuclear mitochondria in mouse parotid acinar cells. J Biol Chem. 2004 Mar 26; 279(13):12909-17.
    View in: PubMed
  31. Shuttleworth TJ, Mignen O. Calcium entry and the control of calcium oscillations. Biochem Soc Trans. 2003 Oct; 31(Pt 5):916-9.
    View in: PubMed
  32. Mignen O, Thompson JL, Shuttleworth TJ. Calcineurin directs the reciprocal regulation of calcium entry pathways in nonexcitable cells. J Biol Chem. 2003 Oct 10; 278(41):40088-96.
    View in: PubMed
  33. Mignen O, Thompson JL, Shuttleworth TJ. Ca2+ selectivity and fatty acid specificity of the noncapacitative, arachidonate-regulated Ca2+ (ARC) channels. J Biol Chem. 2003 Mar 21; 278(12):10174-81.
    View in: PubMed
  34. Bruce JI, Yule DI, Shuttleworth TJ. Ca2+-dependent protein kinase--a modulation of the plasma membrane Ca2+-ATPase in parotid acinar cells. J Biol Chem. 2002 Dec 13; 277(50):48172-81.
    View in: PubMed
  35. Giovannucci DR, Bruce JI, Straub SV, Arreola J, Sneyd J, Shuttleworth TJ, Yule DI. Cytosolic Ca(2+) and Ca(2+)-activated Cl(-) current dynamics: insights from two functionally distinct mouse exocrine cells. J Physiol. 2002 Apr 15; 540(Pt 2):469-84.
    View in: PubMed
  36. Bruce JI, Shuttleworth TJ, Giovannucci DR, Yule DI. Phosphorylation of inositol 1,4,5-trisphosphate receptors in parotid acinar cells. A mechanism for the synergistic effects of cAMP on Ca2+ signaling. J Biol Chem. 2002 Jan 11; 277(2):1340-8.
    View in: PubMed
  37. Mignen O, Thompson JL, Shuttleworth TJ. Reciprocal regulation of capacitative and arachidonate-regulated noncapacitative Ca2+ entry pathways. J Biol Chem. 2001 Sep 21; 276(38):35676-83.
    View in: PubMed
  38. Mignen O, Shuttleworth TJ. Permeation of monovalent cations through the non-capacitative arachidonate-regulated Ca2+ channels in HEK293 cells. Comparison with endogenous store-operated channels. J Biol Chem. 2001 Jun 15; 276(24):21365-74.
    View in: PubMed
  39. Mignen O, Shuttleworth TJ. I(ARC), a novel arachidonate-regulated, noncapacitative Ca(2+) entry channel. J Biol Chem. 2000 Mar 31; 275(13):9114-9.
    View in: PubMed
  40. Osterhout JL, Shuttleworth TJ. A Ca(2+)-independent activation of a type IV cytosolic phospholipase A(2) underlies the receptor stimulation of arachidonic acid-dependent noncapacitative calcium entry. J Biol Chem. 2000 Mar 17; 275(11):8248-54.
    View in: PubMed
  41. Shuttleworth TJ, Thompson JL. Discriminating between capacitative and arachidonate-activated Ca(2+) entry pathways in HEK293 cells. J Biol Chem. 1999 Oct 29; 274(44):31174-8.
    View in: PubMed
  42. Shuttleworth TJ, Hildebrandt JP. Vertebrate salt glands: short- and long-term regulation of function. J Exp Zool. 1999 Jun 1; 283(7):689-701.
    View in: PubMed
  43. Shuttleworth TJ. What drives calcium entry during [Ca2+]i oscillations?--challenging the capacitative model. Cell Calcium. 1999 Mar; 25(3):237-46.
    View in: PubMed
  44. Shuttleworth TJ, Thompson JL. Muscarinic receptor activation of arachidonate-mediated Ca2+ entry in HEK293 cells is independent of phospholipase C. J Biol Chem. 1998 Dec 4; 273(49):32636-43.
    View in: PubMed
  45. Shuttleworth TJ. Intracellular Ca2+ signalling in secretory cells. J Exp Biol. 1997 Jan; 200(Pt 2):303-14.
    View in: PubMed
  46. Martin SC, Shuttleworth TJ. The control of fluid-secreting epithelia by VIP. Ann N Y Acad Sci. 1996 Dec 26; 805:133-47; discussion 147-8.
    View in: PubMed
  47. Wu JV, Shuttleworth TJ, Stampe P. Clustered distribution of calcium sensitivities: an indication of hetero-tetrameric gating components in Ca2+-activated K+ channels reconstituted from avian nasal gland cells. J Membr Biol. 1996 Dec; 154(3):275-82.
    View in: PubMed
  48. Shuttleworth TJ. Arachidonic acid activates the noncapacitative entry of Ca2+ during [Ca2+]i oscillations. J Biol Chem. 1996 Sep 6; 271(36):21720-5.
    View in: PubMed
  49. Shuttleworth TJ, Thompson JL. Evidence for a non-capacitative Ca2+ entry during [Ca2+] oscillations. Biochem J. 1996 Jun 15; 316 ( Pt 3):819-24.
    View in: PubMed
  50. Shuttleworth TJ, Thompson JL. Ca2+ entry modulates oscillation frequency by triggering Ca2+ release. Biochem J. 1996 Feb 1; 313 ( Pt 3):815-9.
    View in: PubMed
  51. Shuttleworth TJ. A re-evaluation of the apparent effects of luminal Ca2+ on inositol 1,4,5-trisphosphate-induced Ca2+ release. Cell Calcium. 1995 Jun; 17(6):393-8.
    View in: PubMed
  52. Martin SC, Shuttleworth TJ. Activation by ATP of a P2U 'nucleotide' receptor in an exocrine cell. Br J Pharmacol. 1995 May; 115(2):321-9.
    View in: PubMed
  53. Martin SC, Shuttleworth TJ. Ca2+ influx drives agonist-activated [Ca2+]i oscillations in an exocrine cell. FEBS Lett. 1994 Sep 19; 352(1):32-6.
    View in: PubMed
  54. Martin SC, Shuttleworth TJ. Vasoactive intestinal peptide stimulates a cAMP-mediated Cl- current in avian salt gland cells. Regul Pept. 1994 Aug 4; 52(3):205-14.
    View in: PubMed
  55. Martin SC, Thompson J, Shuttleworth TJ. Potentiation of Ca(2+)-activated secretory activity by a cAMP-mediated mechanism in avian salt gland cells. Am J Physiol. 1994 Jul; 267(1 Pt 1):C255-65.
    View in: PubMed
  56. Shuttleworth TJ. Temporal relationships between Ca2+ store mobilization and Ca2+ entry in an exocrine cell. Cell Calcium. 1994 Jun; 15(6):457-66.
    View in: PubMed
  57. Hildebrandt JP, Shuttleworth TJ. Muscarinic receptor characterization in differentiating avian exocrine cells. Am J Physiol. 1994 Mar; 266(3 Pt 2):R674-81.
    View in: PubMed
  58. Martin SC, Shuttleworth TJ. Muscarinic-receptor activation stimulates oscillations in K+ and Cl- currents which are acutely dependent on extracellular Ca2+ in avian salt gland cells. Pflugers Arch. 1994 Feb; 426(3-4):231-8.
    View in: PubMed
  59. Hildebrandt JP, Shuttleworth TJ. A Gq-type G protein couples muscarinic receptors to inositol phosphate and calcium signaling in exocrine cells from the avian salt gland. J Membr Biol. 1993 Apr; 133(2):183-90.
    View in: PubMed
  60. Shuttleworth TJ, Thompson JL. Modulation of inositol(1,4,5)trisphosphate-sensitive calcium store content during continuous receptor activation and its effects on calcium entry. Cell Calcium. 1992 Oct; 13(9):541-51.
    View in: PubMed
  61. Hildebrandt JP, Shuttleworth TJ. Calcium-sensitivity of inositol 1,4,5-trisphosphate metabolism in exocrine cells from the avian salt gland. Biochem J. 1992 Mar 15; 282 ( Pt 3):703-10.
    View in: PubMed
  62. Shuttleworth TJ. Ca2+ release from inositol trisphosphate-sensitive stores is not modulated by intraluminal [Ca2+]. J Biol Chem. 1992 Feb 25; 267(6):3573-6.
    View in: PubMed
  63. Shuttleworth TJ, Wood CM. Changes in pHi associated with activation of ion secretion in avian nasal salt gland cells. Am J Physiol. 1992 Jan; 262(1 Pt 1):C221-8.
    View in: PubMed
  64. Hildebrandt JP, Shuttleworth TJ. Inositol phosphates and [Ca2+]i signals in a differentiating exocrine cell. Am J Physiol. 1991 Aug; 261(2 Pt 1):C210-7.
    View in: PubMed
  65. Shuttleworth TJ, Thompson JL. Effect of temperature on receptor-activated changes in [Ca2+]i and their determination using fluorescent probes. J Biol Chem. 1991 Jan 25; 266(3):1410-4.
    View in: PubMed
  66. Shuttleworth TJ. Fluoroaluminate activation of different components of the calcium signal in an exocrine cell. Biochem J. 1990 Jul 15; 269(2):417-22.
    View in: PubMed
  67. Shuttleworth TJ. Receptor-activated calcium entry in exocrine cells does not occur via agonist-sensitive intracellular pools. Biochem J. 1990 Mar 15; 266(3):719-26.
    View in: PubMed
  68. Shuttleworth TJ, Thompson JL. Intracellular [Ca2+] and inositol phosphates in avian nasal gland cells. Am J Physiol. 1989 Nov; 257(5 Pt 1):C1020-9.
    View in: PubMed
  69. Dimaline R, Young J, Thwaites DT, Lee CM, Shuttleworth TJ, Thorndyke MC. A novel vasoactive intestinal peptide (VIP) from elasmobranch intestine has full affinity for mammalian pancreatic VIP receptors. Biochim Biophys Acta. 1987 Aug 19; 930(1):97-100.
    View in: PubMed
  70. Shuttleworth TJ, Thompson JL, Dantzler WH. Potassium secretion by nasal salt glands of desert lizard Sauromalus obesus. Am J Physiol. 1987 Jul; 253(1 Pt 2):R83-90.
    View in: PubMed
  71. Shuttleworth TJ, Thompson JL. Secretory activity in salt glands of birds and turtles: stimulation via cyclic AMP. Am J Physiol. 1987 Feb; 252(2 Pt 2):R428-32.
    View in: PubMed
  72. Stagg RM, Shuttleworth TJ. Sites of interactions of surfactants with beta-adrenergic responses in trout (Salmo gairdneri) gills. J Comp Physiol B. 1987; 157(4):429-34.
    View in: PubMed
  73. Davis MS, Shuttleworth TJ. Mode of adrenergic and peptidergic inhibition of ion transport in flounder gill. Am J Physiol. 1986 Dec; 251(6 Pt 2):R1064-70.
    View in: PubMed
  74. Shuttleworth TJ, Thompson JL. Perfusion-secretion relationships in the isolated elasmobranch rectal gland. J Exp Biol. 1986 Sep; 125:373-84.
    View in: PubMed
  75. Davis MS, Shuttleworth TJ. Pancreatic peptides regulate Cl- secretion in the marine teleost gill. Peptides. 1985; 6 Suppl 3:379-82.
    View in: PubMed
  76. Thorndyke MC, Shuttleworth TJ. Biochemical and physiological studies on peptides from the elasmobranch gut. Peptides. 1985; 6 Suppl 3:369-72.
    View in: PubMed
  77. Shuttleworth TJ, Thorndyke MC. An endogenous peptide stimulates secretory activity in the elasmobranch rectal gland. Science. 1984 Jul 20; 225(4659):319-21.
    View in: PubMed
  78. Shuttleworth TJ, Goldstein L. Beta-alanine transport in the isolated hepatocytes of the elasmobranch Raja erinacea. J Exp Zool. 1984 Jul; 231(1):39-44.
    View in: PubMed
  79. Stagg RM, Shuttleworth TJ. Hemodynamics and potentials in isolated flounder gills: effects of catecholamines. Am J Physiol. 1984 Feb; 246(2 Pt 2):R211-20.
    View in: PubMed
  80. Shuttleworth TJ. Role of calcium in cAMP-mediated effects in the elasmobranch rectal gland. Am J Physiol. 1983 Dec; 245(6):R894-900.
    View in: PubMed
  81. Shuttleworth TJ. Haemodynamic effects of secretory agents on the isolated elasmobranch rectal gland. J Exp Biol. 1983 Mar; 103:193-204.
    View in: PubMed
  82. Shuttleworth TJ. Amphotericin B and the elasmobranch rectal gland: implications for the relationship between oxygen consumption and ion transport. J Exp Zool. 1982 Jun 10; 221(2):255-8.
    View in: PubMed
  83. Shuttleworth TJ, Freeman RF. Net fluxes of water in the isolated gills of Anguilla dieffenbachii. J Exp Biol. 1974 Jun; 60(3):769-81.
    View in: PubMed
  84. Shuttleworth TJ. A new isolated perfused gill preparation for the study of the mechanisms of ionic regulation in teleosts. Comp Biochem Physiol A Comp Physiol. 1972 Sep 1; 43(1):59-64.
    View in: PubMed

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