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Donald L. Gill, PhD

TitleProfessor and Chair of Cellular and Molecular Physiology
InstitutionCollege of Medicine
DepartmentCellular and Molecular Physiology
Address500 University Drive Hershey, PA 17033
Phone717-531-8567

 Overview 
 overview
PREFERRED TITLE/ROLE:

Professor and Chair of Cellular and Molecular Physiology


EDUCATION:

Ph.D., University of London, England, 1979
Postdoctoral Training, National Institutes of Health, 1979-1982

NARRATIVE:

Calcium is one of the most fundamental signaling agents in all animal cells. Cells have evolved to precisely control Ca2+ in the cytoplasm at levels that are 10,000-fold lower than outside cells. This is accomplished by Ca2+ pumps in the plasma membrane (PM) and endoplasmic reticulum (ER). We study the signals of Ca2+ which occur as a result of control of specific channels in the PM and ER membrane which allow Ca2+ to flow into the cytosol. A slight elevation in the resting cytosolic Ca2+ level is enough to trigger rapid cellular responses such as contraction, secretion or changes in the function of key metabolic enzymes. More sustained Ca2+ signals mediate crucial longer term responses including cell growth, cell division, and cell death (apoptosis). Our lab studies signal transduction, meaning that we study how cells transduce external signals into Ca2+ signals. Cells sense many different external signals through specific receptors for chemical agents such as growth factors, neurotransmitters, and hormones, as well as receptors for temperature, pressure, stretch, sound, and light. The cell converts the message received by receptors into Ca2+ signals by precisely controlling the opening of Ca2+ channels. We use a combination of molecular biology, biochemistry, cell biology, and single cell physiological approaches to understand how the Ca2+ channels are controlled. We use molecular biology to mutate the channel proteins, create expression vectors, and to modify channel expression using gene silencing approaches. We follow real-time Ca2+ signals in cells using sophisticated single cell ratiometric fluorescence imaging technology. And we measure the precise biophysical properties of channels using state-of the-art electrophysiological methods. The work centers on the analysis of several distinct types of membrane channels including members of the now widely recognized TRP family of channel proteins involved in transducing a remarkable array of external signals. More recently, we have focused on understanding the mechanisms by which STIM and Orai proteins are involved in the controlling Ca2+ signals. Our work draws together molecular and cellular approaches to understand the basic function and physiological role of these channels which are critical to mediating essential cellular responses.


 Bibliographic 
 selected publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Shanmughapriya S, Rajan S, Hoffman NE, Zhang X, Guo S, Kolesar JE, Hines KJ, Ragheb J, Jog NR, Caricchio R, Baba Y, Zhou Y, Kaufman BA, Cheung JY, Kurosaki T, Gill DL, Madesh M. Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU. Sci Signal. 2015; 8(366):ra23.
    View in: PubMed
  2. Hendron E, Wang X, Zhou Y, Cai X, Goto J, Mikoshiba K, Baba Y, Kurosaki T, Wang Y, Gill DL. Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs. Cell Calcium. 2014 Dec; 56(6):482-92.
    View in: PubMed
  3. Wang X, Wang Y, Zhou Y, Hendron E, Mancarella S, Andrake MD, Rothberg BS, Soboloff J, Gill DL. Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. Nat Commun. 2014; 5:3183.
    View in: PubMed
  4. Rothberg BS, Wang Y, Gill DL. Orai channel pore properties and gating by STIM: implications from the Orai crystal structure. Sci Signal. 2013; 6(267):pe9.
    View in: PubMed
  5. Gandhirajan RK, Meng S, Chandramoorthy HC, Mallilankaraman K, Mancarella S, Gao H, Razmpour R, Yang XF, Houser SR, Chen J, Koch WJ, Wang H, Soboloff J, Gill DL, Madesh M. Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. J Clin Invest. 2013 Feb 1; 123(2):887-902.
    View in: PubMed
  6. Mancarella S, Potireddy S, Wang Y, Gao H, Gandhirajan RK, Autieri M, Scalia R, Cheng Z, Wang H, Madesh M, Houser SR, Gill DL. Targeted STIM deletion impairs calcium homeostasis, NFAT activation, and growth of smooth muscle. FASEB J. 2013 Mar; 27(3):893-906.
    View in: PubMed
  7. Soboloff J, Rothberg BS, Madesh M, Gill DL. STIM proteins: dynamic calcium signal transducers. Nat Rev Mol Cell Biol. 2012 Sep; 13(9):549-65.
    View in: PubMed
  8. Robinson LJ, Mancarella S, Songsawad D, Tourkova IL, Barnett JB, Gill DL, Soboloff J, Blair HC. Gene disruption of the calcium channel Orai1 results in inhibition of osteoclast and osteoblast differentiation and impairs skeletal development. Lab Invest. 2012 Jul; 92(7):1071-83.
    View in: PubMed
  9. Mancarella S, Wang Y, Deng X, Landesberg G, Scalia R, Panettieri RA, Mallilankaraman K, Tang XD, Madesh M, Gill DL. Hypoxia-induced acidosis uncouples the STIM-Orai calcium signaling complex. J Biol Chem. 2011 Dec 30; 286(52):44788-98.
    View in: PubMed
  10. Li C, Li J, Cai X, Sun H, Jiao J, Bai T, Zhou XW, Chen X, Gill DL, Tang XD. Protein kinase D3 is a pivotal activator of pathological cardiac hypertrophy by selectively increasing the expression of hypertrophic transcription factors. J Biol Chem. 2011 Nov 25; 286(47):40782-91.
    View in: PubMed
  11. Soboloff J, Madesh M, Gill DL. Sensing cellular stress through STIM proteins. Nat Chem Biol. 2011 Aug; 7(8):488-92.
    View in: PubMed
  12. Mancarella S, Wang Y, Gill DL. Signal transduction: STIM1 senses both Ca²+ and heat. Nat Chem Biol. 2011 Jun; 7(6):344-5.
    View in: PubMed
  13. Li C, Cai X, Sun H, Bai T, Zheng X, Zhou XW, Chen X, Gill DL, Li J, Tang XD. The dA isoform of calmodulin kinase II mediates pathological cardiac hypertrophy by interfering with the HDAC4-MEF2 signaling pathway. Biochem Biophys Res Commun. 2011 May 27; 409(1):125-30.
    View in: PubMed
  14. Wang Y, Deng X, Gill DL. Calcium signaling by STIM and Orai: intimate coupling details revealed. Sci Signal. 2010; 3(148):pe42.
    View in: PubMed
  15. Wang Y, Deng X, Mancarella S, Hendron E, Eguchi S, Soboloff J, Tang XD, Gill DL. The calcium store sensor, STIM1, reciprocally controls Orai and CaV1.2 channels. Science. 2010 Oct 1; 330(6000):105-9.
    View in: PubMed
  16. Hawkins BJ, Irrinki KM, Mallilankaraman K, Lien YC, Wang Y, Bhanumathy CD, Subbiah R, Ritchie MF, Soboloff J, Baba Y, Kurosaki T, Joseph SK, Gill DL, Madesh M. S-glutathionylation activates STIM1 and alters mitochondrial homeostasis. J Cell Biol. 2010 Aug 9; 190(3):391-405.
    View in: PubMed
  17. Mancarella S, Wang Y, Gill DL. Calcium signals: STIM dynamics mediate spatially unique oscillations. Curr Biol. 2009 Nov 3; 19(20):R950-2.
    View in: PubMed
  18. Zhou Y, Mancarella S, Wang Y, Yue C, Ritchie M, Gill DL, Soboloff J. The short N-terminal domains of STIM1 and STIM2 control the activation kinetics of Orai1 channels. J Biol Chem. 2009 Jul 17; 284(29):19164-8.
    View in: PubMed
  19. Deng X, Wang Y, Zhou Y, Soboloff J, Gill DL. STIM and Orai: dynamic intermembrane coupling to control cellular calcium signals. J Biol Chem. 2009 Aug 21; 284(34):22501-5.
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  20. Wang Y, Deng X, Zhou Y, Hendron E, Mancarella S, Ritchie MF, Tang XD, Baba Y, Kurosaki T, Mori Y, Soboloff J, Gill DL. STIM protein coupling in the activation of Orai channels. Proc Natl Acad Sci U S A. 2009 May 5; 106(18):7391-6.
    View in: PubMed
  21. Graham SJ, Black MJ, Soboloff J, Gill DL, Dziadek MA, Johnstone LS. Stim1, an endoplasmic reticulum Ca2+ sensor, negatively regulates 3T3-L1 pre-adipocyte differentiation. Differentiation. 2009 Mar; 77(3):239-47.
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  22. Wang Y, Deng X, Hewavitharana T, Soboloff J, Gill DL. Stim, ORAI and TRPC channels in the control of calcium entry signals in smooth muscle. Clin Exp Pharmacol Physiol. 2008 Sep; 35(9):1127-33.
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  23. Hewavitharana T, Deng X, Wang Y, Ritchie MF, Girish GV, Soboloff J, Gill DL. Location and function of STIM1 in the activation of Ca2+ entry signals. J Biol Chem. 2008 Sep 19; 283(38):26252-62.
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  24. Spassova MA, Hewavitharana T, Fandino RA, Kaya A, Tanaka J, Gill DL. Voltage gating at the selectivity filter of the Ca2+ release-activated Ca2+ channel induced by mutation of the Orai1 protein. J Biol Chem. 2008 May 30; 283(22):14938-45.
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  25. Parvez S, Beck A, Peinelt C, Soboloff J, Lis A, Monteilh-Zoller M, Gill DL, Fleig A, Penner R. STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation. FASEB J. 2008 Mar; 22(3):752-61.
    View in: PubMed
  26. Hewavitharana T, Deng X, Soboloff J, Gill DL. Role of STIM and Orai proteins in the store-operated calcium signaling pathway. Cell Calcium. 2007 Aug; 42(2):173-82.
    View in: PubMed
  27. Ong HL, Cheng KT, Liu X, Bandyopadhyay BC, Paria BC, Soboloff J, Pani B, Gwack Y, Srikanth S, Singh BB, Gill DL, Gill D, Ambudkar IS. Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx. Evidence for similarities in store-operated and calcium release-activated calcium channel components. J Biol Chem. 2007 Mar 23; 282(12):9105-16.
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  28. Spassova MA, Hewavitharana T, Xu W, Soboloff J, Gill DL. A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Proc Natl Acad Sci U S A. 2006 Oct 31; 103(44):16586-91.
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  29. Soboloff J, Spassova MA, Dziadek MA, Gill DL. Calcium signals mediated by STIM and Orai proteins--a new paradigm in inter-organelle communication. Biochim Biophys Acta. 2006 Nov; 1763(11):1161-8.
    View in: PubMed
  30. Vig M, Beck A, Billingsley JM, Lis A, Parvez S, Peinelt C, Koomoa DL, Soboloff J, Gill DL, Fleig A, Kinet JP, Penner R. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr Biol. 2006 Oct 24; 16(20):2073-9.
    View in: PubMed
  31. Soboloff J, Spassova MA, Hewavitharana T, He LP, Xu W, Johnstone LS, Dziadek MA, Gill DL. STIM2 is an inhibitor of STIM1-mediated store-operated Ca2+ Entry. Curr Biol. 2006 Jul 25; 16(14):1465-70.
    View in: PubMed
  32. Gill DL, Spassova MA, Soboloff J. Signal transduction. Calcium entry signals--trickles and torrents. Science. 2006 Jul 14; 313(5784):183-4.
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  33. Soboloff J, Spassova MA, Tang XD, Hewavitharana T, Xu W, Gill DL. Orai1 and STIM reconstitute store-operated calcium channel function. J Biol Chem. 2006 Jul 28; 281(30):20661-5.
    View in: PubMed
  34. Spassova MA, Soboloff J, He LP, Xu W, Dziadek MA, Gill DL. STIM1 has a plasma membrane role in the activation of store-operated Ca(2+) channels. Proc Natl Acad Sci U S A. 2006 Mar 14; 103(11):4040-5.
    View in: PubMed
  35. Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH. Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling. Trends Biochem Sci. 2005 Dec; 30(12):688-97.
    View in: PubMed
  36. Soboloff J, Spassova M, Xu W, He LP, Cuesta N, Gill DL. Role of endogenous TRPC6 channels in Ca2+ signal generation in A7r5 smooth muscle cells. J Biol Chem. 2005 Dec 2; 280(48):39786-94.
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  37. van Rossum DB, Patterson RL, Sharma S, Barrow RK, Kornberg M, Gill DL, Snyder SH. Phospholipase Cgamma1 controls surface expression of TRPC3 through an intermolecular PH domain. Nature. 2005 Mar 3; 434(7029):99-104.
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  38. He LP, Hewavitharana T, Soboloff J, Spassova MA, Gill DL. A functional link between store-operated and TRPC channels revealed by the 3,5-bis(trifluoromethyl)pyrazole derivative, BTP2. J Biol Chem. 2005 Mar 25; 280(12):10997-1006.
    View in: PubMed
  39. Spassova MA, Soboloff J, He LP, Hewavitharana T, Xu W, Venkatachalam K, van Rossum DB, Patterson RL, Gill DL. Calcium entry mediated by SOCs and TRP channels: variations and enigma. Biochim Biophys Acta. 2004 Dec 6; 1742(1-3):9-20.
    View in: PubMed
  40. Gill DL, Patterson RL. Toward a consensus on the operation of receptor-induced calcium entry signals. Sci STKE. 2004 Jul 27; 2004(243):pe39.
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  41. van Rossum DB, Patterson RL, Kiselyov K, Boehning D, Barrow RK, Gill DL, Snyder SH. Agonist-induced Ca2+ entry determined by inositol 1,4,5-trisphosphate recognition. Proc Natl Acad Sci U S A. 2004 Feb 24; 101(8):2323-7.
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  42. Venkatachalam K, Zheng F, Gill DL. Control of TRPC and store-operated channels by protein kinase C. Novartis Found Symp. 2004; 258:172-85; discussion 185-8, 263-6.
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  43. Ma HT, Venkatachalam K, Rys-Sikora KE, He LP, Zheng F, Gill DL. Modification of phospholipase C-gamma-induced Ca2+ signal generation by 2-aminoethoxydiphenyl borate. Biochem J. 2003 Dec 15; 376(Pt 3):667-76.
    View in: PubMed
  44. Venkatachalam K, Zheng F, Gill DL. Regulation of canonical transient receptor potential (TRPC) channel function by diacylglycerol and protein kinase C. J Biol Chem. 2003 Aug 1; 278(31):29031-40.
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  45. Patterson RL, van Rossum DB, Ford DL, Hurt KJ, Bae SS, Suh PG, Kurosaki T, Snyder SH, Gill DL. Phospholipase C-gamma is required for agonist-induced Ca2+ entry. Cell. 2002 Nov 15; 111(4):529-41.
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  46. Venkatachalam K, van Rossum DB, Patterson RL, Ma HT, Gill DL. The cellular and molecular basis of store-operated calcium entry. Nat Cell Biol. 2002 Nov; 4(11):E263-72.
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  47. Ma HT, Venkatachalam K, Parys JB, Gill DL. Modification of store-operated channel coupling and inositol trisphosphate receptor function by 2-aminoethoxydiphenyl borate in DT40 lymphocytes. J Biol Chem. 2002 Mar 1; 277(9):6915-22.
    View in: PubMed
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