RESEARCH DESCRIPTION

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 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).  My laboratory 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.  My lab uses 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 by 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.  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. 

Selected Publications:

Soboloff, J., Spassova, M.A., Xu, W., He, L-P., Cuesta, N., and Gill, D.L. (2005) “Role of endogenous TRPC6 channels in Ca²⁺ signal generation in A7r5 smooth muscle cells”  J. Biol. Chem.  280, 39786-39794

Patterson, R.L., van Rossum, D.B., Nikolaidis, N., Gill, D.L., and Snyder, S.H. (2005) “Phospholipase C: Diverse Roles in Receptor-Mediated Calcium Signaling”  TIBS  30, 688-697

 van Rossum, D.B., Patterson, R.L., Sharma, S., Barrow, R.K., Kornberg, M., Gill, D.L., and Snyder, S.H. (2005)  PLC-g1 Controls Plasma Membrane Retention of TRPC3: Evidence for Intermolecular PH Domains.  Nature  434, 99-104

He, L-P, Hewavitharana, T., Soboloff, J., Spassova, M.A., and Gill, D.L. (2005)  A functional link between store-operated and TRPC channels revealed by the 3,5-bistrifluoro­methyl-pyrazole derivative, BTP2.  J. Biol. Chem.  280, 10997-11006

 Patterson, R.L., and Gill, D.L. (2004)  “Toward a consensus on the operation of receptor-induced calcium entry signals”  Science STKE. 243, 39-43

Seth, M., Sumbilla, C., Mullen, S.P., Lewis, D., Klein, M.G., Hussain, A., Soboloff, J., Gill, D.L., and Inesi, G. (2004)  Ca²⁺ ATPase (SERCA) gene silencing and remodeling of the Ca²⁺ signaling mechanism in cardiac myocytes.  Proc. Natl. Acad. Sci. USA  101, 16683-16688

 Spassova, M.A., Soboloff, J., He, L-H., Hewavitharana, T., Xu, W., Venkatachalam, K., van Rossum D.B., Patterson, R.L., and Gill, D.L. (2004) “Calcium entry mediated by SOCs and TRP channels: variations and enigma”  Biochem. Biophys. Acta 174, 9-20

van Rossum, D.B., Patterson, R.L., Kiselyov, K., Boehning, D., Barrow, R., Gill, D.L., and Snyder, S.H., (2004)  “Agonist-induced Ca²⁺ entry determined by inositol 1,4,5-trisphosphate recognition”  Proc. Natl. Acad. Sci. USA, 101, 2323-2327

Venkatachalam, K., Zheng, F., and Gill, D.L. (2003)  “Regulation of canonical transient receptor potential (TRPC) channel function by diacylglycerol and PKC”  J. Biol. Chem. 278, 29031-29040

Ma, H-T., Venkatachalam, K., Rys-Sikora, K.E., He, L-P., Zheng, F., and Gill, D.L. (2003)  “Modification of phospholipase C-gamma-induced Ca 2+ signal-generation by 2-aminoethoxydiphenyl borate”  Biochem. J. 376,  667-676

Patterson, R.L., van Rossum, D.B., Ford, D.L., Hurt, K.J., Bae, S.S., Suh-P-G., Kurosaki, T., Snyder, S.H., and Gill, D.L. (2002)  “Phospholipase C-γ is required for agonist induced Ca²⁺ entry”  Cell  111, 529-541

Venkatachalam, K., van Rossum, D.B., Patterson, R.L., Ma, H-T and Gill, D.L (2002)  “The cellular and molecular basis of store-operated calcium entry”   Nature Cell Biol.  11, (263-272

Ma, H-T., Venkatachalam, K., Parys, J.B., and Gill, D.L. (2002)  Modification of store-operated channel-coupling and InsP₃ receptor-function by 2-aminoethoxy­diphenyl borate in DT40 lymphocytes.  J. Biol. Chem.  277, 6915-6922

Venkatachalam, K., Ma, H-T., Ford, D.L., and Gill, D.L. (2001)  “Expression of functional receptor-coupled TRPC3 channels in DT40 triple InsP₃ receptor knockout cells” J. Biol. Chem.  276, 33980-33985.

Xu, X-Z., Moebius, F., Gill, D.L., and Montell ,C.  (2001)  “Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoforms”  Proc. Natl. Acad. Sci. USA. 98, 10692-10697

Ma, H.T., Venkatachalam, K., Li, H.S., Montell, C., Kurosaki, T., Patterson, R.L., and Gill, D.L. (2001)   “Assessment of the role of the inositol 1,4,5-trisphosphate receptor in the activation of transient receptor potential channels and store-operated Ca²⁺ entry channels”   J. Biol. Chem.  276, 18888-18896.

Chorna-Ornan, I., Joel-Almagor, T., Ben-Ami, H.C., Frechter, S., Gillo, B., Selinger Z, Gill, D.L., and Minke, B. (2001)  “A common mechanism underlies vertebrate calcium signaling and Drosophila phototransduction”  J. Neurosci.  21, 2622-2629

Ma, H-T., Patterson, R.L., van Rossum, D.B., Birnbaumer, L., Mikoshiba, K., and  Gill, D.L. (2000)  “Requirement of the inositol trisphosphate receptor for activation of store-operated Ca²⁺ channels”  Science  287, 1647-1651

van Rossum, D.B., Patterson, R.L., Ma, H-T., and Gill, D.L. (2000) “Ca²⁺ entry mediated by store-depletion, S-nitrosylation, and TRP3 channels:  comparison of coupling and function”  J. Biol. Chem.  275, 28562-28568

 Patterson, R.L., van Rossum, D.B., and Gill, D.L. (1999)  “Store-operated Ca²⁺ entry: evidence for a secretion-like coupling mechanism”  Cell  98, 487-499