Michael D. Cahalan

picture of Michael D. Cahalan

Distinguished Professor and Chair, Physiology & Biophysics
School of Medicine

Ph.D., University of Washington, 1974, Physiology and Biophysics, thesis research with Bertil Hille

Phone: (949) 824-7776
Email: mcahalan@uci.edu

University of California, Irvine
Department of Physiology and Biophysics
285 Irvine Hall
Irvine, CA 92697
Research Interests
Ion Channels, Calcium Signaling, T Lymphocytes, Imaging, Cell Motility and Interaction Dynamics
Academic Distinctions
1970: Graduated Oberlin College Phi Beta Kappa, Magna cum laude
1976: Muscular Dystrophy Association Postdoctoral Fellowship
1981: NIH Research Career Development Award
1989-90: Alexander von Humboldt Senior Scientist Prize
1991-95, 2006-present: Department Chair
1997: Athalie Clark Research Achievement Award
1998: Elected President, Society of General Physiologists
2000: Kenneth S. Cole Award in Membrane Biophysics
2006-13: Javits Neuroscience Investigator Award
2008: Elected to the Henry Kunkel Society
2009,11,13: Excellence in Teaching Award from medical students
2010: Elected to the U.S. National Academy of Sciences
2011: UCI Distinguished Faculty Award for Research
postdoctoral research with Clay Armstrong, University of Pennsylvania, 1974-1977
Research Abstract
Cahalan’s pioneering work identified the pivotal role of ion channels in the immune response. He elucidated the physiological functions and the molecular basis for calcium signaling that activates T lymphocytes. By imaging in lymphoid organs, his work has also revealed an elegant cellular choreography that underlies the initiation of the immune response in vivo.

Ion Channels in the Immune System. Cahalan’s group discovered the biophysical phenotype and molecular properties of ion channel types in T lymphocytes. His work shows that ion channel types play vital roles in T cell activation, cell motility, and cell volume regulation. A voltage-gated potassium channel (Kv1.3) shows great promise as a therapeutic target for treatment of inflammatory and autoimmune disorders, with proven efficacy in animal models of multiple sclerosis, rheumatoid arthritis and delayed type hypersensitivity. Calcium is a vital second messenger in lymphocytes. Cahalan’s work provided the electrophysiological signature of calcium entry triggered by antigen. His single-cell imaging experiments decoded the intracellular calcium signaling requirements for gene transcriptional activation and cell motility in lymphocytes. Of particular note, using an RNAi screening approach he identified two proteins, STIM and Orai, that together form the molecular basis for store-operated calcium channel activity. By mutational analysis, Cahalan showed that STIM functions as the Ca2+ sensor in the endoplasmic reticulum, as the messenger to the plasma membrane, and as the effector molecule that activates Ca2+ influx. The Cahalan group carried out a critical genome-wide RNAi screen that led to the co-discovery of the Ca2+ channel-forming protein Orai. His recent work proved that Orai embodies the pore of the calcium channel. These discoveries were noted by Science magazine as “Cell Signaling Breakthroughs of the Year” in 2005 and 2006.

Immunoimaging. Cahalan’s group, together with Ian Parker, pioneered the use of two-photon microscopy to image cell motility and interaction dynamics inside lymphoid organs. T and B cells are highly motile in their native habitat and this plays an important role in locating and responding to antigen. During the initiation of an immune response, T cells interact with and respond to dendritic cells, forming clusters; whereas individual T cells pair up with individual B cells while delivering “help” to trigger antibody production. In vivo imaging approaches, in combination with targeted gene deletion and specific pharmacological agents, are continuing to revealing important insights into the choreography of immune responses in vivo.
Greenberg, M.L., Y. Yu, S. Leverrier, S.L. Zhang, I. Parker, and M.D. Cahalan. 2013. Orai1 function is essential for T cell homing to lymph nodes. Journal of Immunology 190: 3197-3206. PMID 23455504.
My work evolved from graduate and postdoctoral research experience as an electrophysiologist working on neuronal ion channels. As an Assistant Professor, I decided to work on cells of the immune system, originally from my own blood, using a home-built patch-clamp rig to record from small single cells. My research subsequently unfolded in the five main directions outlined below.

Complete list of publications on PubMed: http://www.ncbi.nlm.nih.gov/pubmed/?term=Cahalan+MD

Google citations: https://scholar.google.com/citations?hl=en&user=c0VAUyMAAAAJ

1. Functional network of ion channels in cells of the immune system. Ion channels are well known for generating electrical signals in nerve and muscle cells. We were the first to show that ion channels also contribute to immune system function. We characterized the biophysical and molecular properties of five channel types in T lymphocytes: a voltage-gated K+ channel (Kv1.3), a calcium-activated K+ channel (KCa3.1), a swelling-activated Cl- channel (now identified as Swell1), a nonselective cation channel-kinase (TRPM7), and a store-operated Ca2+ channel (Orai1 activated by STIM1 in the endoplasmic reticulum). Each channel has a unique biophysical fingerprint; each immune cell type and subset have their own channel phenotype. Using ion channel blockers and genetic approaches, we discovered previously unknown functions of ion channels in T lymphocytes to regulate gene expression, cell proliferation, differentiation, volume regulation, ionic homeostasis, and calcium signaling.

DeCoursey, T.E., K.G. Chandy, S. Gupta, and M.D. Cahalan. 1984. Voltage-gated K channels in human T lymphocytes: a role in mitogenesis? Nature 307: 465-468. (cover illustration). PMID: 6320007.

Cahalan, M.D., K.G. Chandy, T.E. DeCoursey, and S. Gupta. 1985. A voltage-gated K+ channel in human T lymphocytes. J Physiol 358: 197-237. PMC1193339.

DeCoursey, T.E., K.G. Chandy, S. Gupta, and M.D. Cahalan. 1985. Voltage-dependent ion channels in T lymphocytes. Journal of Neuroimmunology 10: 71-85. PMID: 2414315.

DeCoursey, T.E., K.G. Chandy, S. Gupta, and M.D. Cahalan. 1987. Two types of potassium channels in murine T lymphocytes. Journal of General Physiology 89: 379-404. PMID: 2435844.

Lewis, R.S. and M.D. Cahalan. 1988. Subset-specific expression of potassium channels in developing murine T lymphocytes. Science 239: 771-775. (cover illustration). PMID: 2448877.

Cahalan, M.D. and R.S. Lewis. 1988. Role of potassium and chloride channels in volume regulation by T lymphocytes. Society of General Physiology Ser. 43: 282-301. PMID: 2479106.

Grissmer, S. and M.D. Cahalan. 1989. TEA prevents inactivation while blocking open K+ channels in human T lymphocytes. Biophysical Journal 55: 203-206. PMID: 2784693.

Grissmer, S. and M.D. Cahalan. 1989. Divalent ion trapping inside potassium channels of human T lymphocytes. Journal of General Physiology 93: 609-630. PMID: 2786551.

McCloskey, M.A. and M.D. Cahalan. 1990. G-protein control of potassium channel activity in a mast cell line. Journal of General Physiology 95: 205-227. PMID: 2106571.

Grissmer, S., R.S. Lewis, and M.D. Cahalan. 1992. Ca2+-activated K+ channels in human leukemic T cells. J Gen Physiol 99: 1-23. PMC2216598.

Grissmer, S., S. Ghanshani, B. Dethlefs, J. McPherson, J. Wasmuth, G. Gutman, M.D. Cahalan, and K.G. Chandy. 1992. The Shaw-related potassium-channel gene, Kv3.1, on human chromosome 11, encodes the type l K+ channel in T Cells. Journal of Biological Chemistry 267: 20971-20979. PMID: 1400413.

Grissmer, S., A.N. Nguyen, and M.D. Cahalan. 1993 Calcium-activated potassium channels in resting and activated human T lymphocytes. Journal of General Physiology 102: 601-630. PMID: 7505804.

Lewis, S., P. Ross, and M.D. Cahalan. 1993. Chloride channels activated by osmotic stress in T lymphocytes. Journal of General Physiology 101: 801-826. PMID: 7687269.

Ross, P., S. Garber, and M.D. Cahalan. 1993. Membrane chloride conductance and capacitance in Jurkat T lymphocytes during osmotic swelling. Biophysical Journal 66: 169-178. PMID: 8130336.

Ehring, G. R., Y.V. Osipchuk, and M.D Cahalan. 1994. Swelling-activated chloride channels in multidrug-sensitive and -resistant cells. Journal of General Physiology 104: 1129-1161. PMID: 7699367.

Verheugen, J.A.H., H.P.M. Vijverberg, M. Oortgiesen, and M.D. Cahalan. 1995. Voltage-gated and Ca2+ -activated K+ channels in intact human T lymphocytes. Journal of General Physiology 13: 765-794. PMID: 7561743

Lewis, R.S. and M.D. Cahalan. 1995. Potassium and calcium channels in lymphocytes. Annual Review of Immunology 13: 623-653. PMID: 7612237.

Lepple-Wienhues, and M.D. Cahalan. 1996. Conductance and permeation of monovalent ions through depletion-activated Ca2+ channels (Icrac) in Jurkat T cells. Biophysical Journal 71: 787-794. PMID: 8842217.

Allen, D., A. Lepple-Wienhues, and M.D. Cahalan. 1997. Ion channel phenotype of melanoma cell lines. J. Membrane Biol. 155: 27-34. PMID: 9002422.

Kerschbaum, H.H. and M.D. Cahalan. 1998. Monovalent permeability, rectification, and ionic block of store-operated calcium channels in Jurkat T lymphocytes. Journal of General Physiology 111: 521-537. PMID: 9524136.

Fanger, C.M., S. Ghanshani, N.J. Logsdon, H. Rauer, K. Kalman, J. Zhou, K. Beckingham, K.G. Chandy, M.D. Cahalan, and J. Aiyar. 1999. Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel, IKCA1. Journal of Biological Chemistry 274: 5746-5754. PMID: 10026195.

Wulff, H., M.D. Cahalan, and K.G. Chandy. 2000. Design of a potent and selective inhibitor of the intermediate conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proceedings of the National Academy of Sciences U.S.A. 97: 8151-8156. PMID: 10884437.

Ghanshani, S., H. Wulff, M.J. Miller, H. Rohm, A.L. Neben, G.A. Gutman, M.D. Cahalan, and K.G. Chandy. 2000. Up-regulation of the IKCa1 potassium channel during T-cell activation: molecular mechanism and functional consequences. Journal of Biological Chemistry 275: 37137-37149. PMID: 10961988.

Kozak, J.A., H.H. Kerschbaum, and M.D. Cahalan. 2002. Distinct properties of CRAC and MIC channels in RBL cells. Journal of General Physiology 120: 8601-8615. PMID: 12149283.

Kozak, J.A. and M.D. Cahalan. 2003. MIC channels are inhibited by internal divalent cations but not ATP. Biophysical Journal 84: 922-927. PMID: 12547774.

Kerschbaum, H.H., J.A. Kozak, and M.D. Cahalan. 2003. Polyvalent cations as permeant probes of MIC and TRPM7 pores. Biophysical Journal 84:2293-305. PMID: 12668438

Matsushita, M., J.A. Kozak, Y. Shimizu, D. McLachlin, H. Yamaguchi, F.Y Wei, K. Tomizawa, H. Matsui, B. Chait, M.D. Cahalan, A.C. Nairn. 2005. Channel function is dissociated from the intrinsic kinase activity and autophosphorylation of TRPM7/CHAK1. Journal of Biological Chemistry 280: 20793-803. PMID: 15781465.

Kozak, J.A., M. Matsushita, A.C. Nairn, and M.D. Cahalan. 2005. Charge screening by internal pH and polyvalent cations as a mechanism for activation, inhibition and rundown of TRPM7/MIC channels. Journal of General Physiology 126:499-514.

Cahalan, M.D. and K.G. Chandy. 2009. The functional network of ion channels in T lymphocytes. Immunological Reviews 231: 59-87. PMC3133616.

2. Kv1.3 from current to clinic for treatment of autoimmune disorders. Our work in collaboration with George Chandy on Kv1.3 potassium channels in T cells has included the following milestones: description of the biophysical fingerprint of a voltage-gated current in T cells; identifying ever more potent and selective blockers, to the picomolar range of affinity; showing that peptide scorpion and sea anemone toxins block the channel like a cork in a bottle; using blockers to identify cellular functions; cloning the gene, identifying effector memory T cells as a vulnerable T cell subset; animal studies, including EAE models, leading to successful Phase 1 and 1B human clinical trials and FDA approval of ShK-186 peptide (dalazatide) to treat autoimmunity. ShK-186 has successfully moved through Phase 1 and 1B trials with an excellent safety profile and efficacy in psoriasis patients. Our studies have identified Kv1.3 in T cells as a potential “Achilles heel” for selective targeting of chronically activated T cells without disrupting acute immune responses to viral or bacterial infection. Phase 2 trials with dalazatide are under development.

Chandy, K.G., T.E. DeCoursey, M.D. Cahalan, C. McLaughlin, S. Gupta. 1984. Voltage-gated potassium channels are required for human T lymphocyte activation. Journal of Experimental Medicine l60: 369-385. PMID: 6088661.

Chandy, K.G., T.E. DeCoursey, M. Fischbach, N. Talal, M.D. Cahalan, and S. Gupta. 1986. Altered K+ channel expression in abnormal T lymphocytes from mice with the lpr gene mutation. Science 233: 1197-1200. PMID: 2426784.

DeCoursey, T.E., K.G. Chandy, S. Gupta, and M.D. Cahalan. 1987. Mitogen induction of ion channels in murine T lymphocytes. Journal of General Physiology 89: 405-420. PMID: 2435845.

Sands, S.B., R.S. Lewis, and M.D. Cahalan. 1989. Charybdotoxin blocks voltage-gated K+ channels in human and murine T lymphocytes. Journal of General Physiology 93: 1061-1074. PMID: 2475579.

Grissmer, S., B. Dethlefs, J. Wasmuth, A.L. Goldin, G.A. Gutman, M.D. Cahalan, and K.G. Chandy. 1990. Expression and chromosomal localization of a lymphocyte K+ channel gene. Proceedings of the National Academy of Sciences U.S.A. 87: 9411-9415. PMID: 2251283.

Nguyen, A., J. Kath, D.C. Hanson, P.C. Kaniff, C. Donovan, R.J. Mather, M. Bruns, B. Dethlefs, H. Rauer, J. Aiyar, A. Lepple-Wienhues, G.A. Gutman, S. Grissmer, M.D. Cahalan, K.G. Chandy. 1996. Novel non-peptide agents block the C-type inactivated conformation of Kv1.3, and suppress T-cell activation. Molecular Pharmacology 50: 1672-1769. PMID: 8967992.

Ehring, G.E., H.H. Kerschbaum, C. Eder, A.L. Neben, C.M. Fanger, R.M. Khoury, P.A. Negulescu, and M.D. Cahalan. 1998. A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes. Journal of Experimental Medicine 188: 1593-1602. PMID: 9802971.

Kalman, K., M.W. Pennington, M.D. Lanigan, A. Nguyen, H. Rauer, V. Mahnir, K. Paschetto, W.R. Kem, S. Grissmer, G.A. Gutman, E.P. Christian, M.D. Cahalan, R.S. Norton, and K.G. Chandy. 1998. ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide. Journal of Biological Chemistry 273: 32697-32707. PMID: 9830012.

Hanson, D.C., A. Nguyen, R.J. Mather, H. Rauer, K. Koch, L.E. Burgess, J.P. Rizzi, C.B. Donovan, M.J. Bruns, P.C. Canniff, A.C. Cunningham, K.A. Verdries, E. Mena, J.C. Kath, G.A. Gutman, M.D. Cahalan, S. Grissmer, K.G. Chandy. 1999. UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation. British Journal of Pharmacology 126:1707-1716. PMID: 10372812.

Rauer, H., M. Pennington, M.D. Cahalan, and K.G. Chandy. 1999. Structural conservation of the pores of calcium-activated and voltage-gated potassium channels determined by a sea anemone toxin. Journal of Biological Chemistry 274: 21885-21892. PMID: 10625664.

Rauer, H., M.D. Lanigan, M.W. Pennington, J. Aiyar, S. Ghanshani, M.D. Cahalan, R.S. Norton, and K.G. Chandy. 2000. Structure-guided transformation of charybdotoxin yields an analog that selectively targets Ca2+-activated over voltage-gated K+ channels. Journal of Biological Chemistry 275: 1201-1208. (cover illustration). PMID: 10625664.

Beeton, C., H. Wulff, J. Barbaria, O. Clot-Faybesse, M. Pennington, D. Bernard, M.D. Cahalan, K.G. Chandy, and E. Beraud. 2001. Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalitis, a model for multiple sclerosis. PNAS 98: 13942-13947. PMC61146.

Fanger, C., H. Rauer, A.L. Neben, M.J. Miller, H. Rauer, H. Wulff, J.C. Rosa, C.R. Ganellin, K.G. Chandy, and M.D. Cahalan. 2001. Calcium-activated potassium channels sustain calcium signaling in T lymphocytes; Selective blockers and manipulated expression levels. Journal of Biological Chemistry 276: 12249-12256. PMID: 11278890.

Beeton, C, H. Wulff, S. Singh, S. Botsko, G. Crossley, G.A. Gutman, M.D. Cahalan, M. Pennington, and K.G. Chandy. 2003. A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes. Journal of Biological Chemistry 278: 9928-9937. PMID: 12511563.

Chandy, K.G., H. Wulff, C. Beeton, M. Pennington, G.A. Gutman, M.D. Cahalan. 2004. K+ channels as targets for specific immunosuppression. Trends in Pharmacological Sciences 25: 280-289. PMC2749963.

Matheu, M.P., C. Beeton, A. Garcia, V. Chi, K. Monaghan, M.I. Uemura, D. Li, S. Pal, L.M. de la Maza, E. Monuki, A. Flugel, M.W. Pennington, I. Parker, K.G. Chandy, and M.D. Cahalan. 2008. Imaging of effector memory T cells during DTH and suppression by Kv1.3 channel block. Immunity 29: 602-614. PMC2732399.

3. Calcium signaling in T lymphocytes. Our contributions to the field of calcium signaling include the first biophysical characterization (in 1989) of the Ca2+ release-activated Ca2+ (CRAC) channel. By single-cell Ca2+ imaging, we showed that cytosolic Ca2+ concentration oscillates within individual T cells following T cell receptor stimulation. In contrast to independent Ca2+ signaling in closely adjacent T cells, mast cell Ca2+ signals spread from cell to cell by purinergic receptors responding to secreted ATP. Sustained Ca2+ influx through CRAC channels requires that the membrane is held at a negative potential by K+ channel activity – both Kv1.3 and KCa3.1 in resting T cells, and predominantly Kv1.3 in effector T cells. We quantitatively determined the time course and Ca2+ dependence of NFAT-driven gene expression, and showed an all-or-none gene expression response in single cells. We also determined the Ca2+ dependence of cellular motility, and showed how T cells remain anchored (STOP signal) to the sites of antigen presentation during formation of the immunological synapse. We also showed that Ca2+ entry takes place locally in T cells at the site of antigen presentation.

Lewis, R.S. and M.D. Cahalan. 1989. Mitogen-induced oscillations of cytosolic Ca2+ and transmembrane Ca2+ current in human leukemic T cells. Cell Regulation 1: 99-112. PMC361429.

Osipchuk, Y. and M. Cahalan. 1992. Cell-to-cell spread of calcium signals mediated by ATP receptors in a mast cell line. Nature 359: 241-244. PMID: 1388246.

Hess, S., M. Oortgiesen, and M.D. Cahalan. 1993 Calcium oscillations in human T and natural killer cells depend upon membrane potential and calcium influx. Journal of Immunology 150: 2620-2633. PMID: 7681076.

Negulescu, P., N. Shastri, and M.D. Cahalan. 1994. Intracellular calcium dependence of IL-2 gene expression in single T lymphocytes. PNAS 91: 2873-2877. PMC43473.

Ross, P.E. and M.D. Cahalan. 1995. Ca2+ influx pathways mediated by swelling and stores depletion in mouse thymocytes. Journal of General Physiology 106: 415-444. PMID: 8786341

Negulescu, P.A., A. Khan, T.B. Krasieva, H.H. Kerschbaum, and M.D. Cahalan. 1996. Polarity of T cell shape, motility, and sensitivity to antigen. Immunity 4: 421-430 (cover illustration) PMID: 8630728.

Ross, P.E., G.R. Ehring, and M.D. Cahalan. 1997. Dynamics of ATP-induced calcium signaling in single mouse thymocytes. Journal of Cell Biology 138: 987-998. PMID: 9281578.

Wei, X., B.J. Tromberg, and M.D. Cahalan. 1999. Mapping the sensitivity of T cells using an optical trap: polarity and minimal number of receptors for Ca2+ signaling. Proceedings of the National Academy of Sciences U.S.A. 96: 8471-8476. PMID: 10411899.

Ehring, G.E., H.H. Kerschbaum, C. Eder, C.M. Fanger, H. Rauer, and M.D. Cahalan. 2000. Vanadate induces calcium signaling, Ca2+ release-activated Ca2+ channel activation, and gene expression in T lymphocytes and RBL-2H3 mast cells via thiol oxidation. Journal of Immunology 164: 679-687. PMID: 10623810.

Fanger, C.M., A. Neben, and M.D. Cahalan. 2000. Differential Ca2+ influx, KCa channel activity and Ca2+ clearance distinguish Th1 and Th2 lymphocytes. Journal of Immunology 164: 1153-1160. PMID: 10640725.

Leissring, M.A., Y. Akbari, C.M. Fanger, M.D. Cahalan, M.P. Mattson, and F.M. LaFerla. 2000. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knock-in mice. Journal of Cell Biology 149: 793-797. PMID: 10811821.

Fanger, C., H. Rauer, A.L. Neben, M.J. Miller, H. Rauer, H. Wulff, J.C. Rosa, C.R. Ganellin, K.G. Chandy, and M.D. Cahalan. 2001. Calcium-activated potassium channels sustain calcium signaling in T lymphocytes; Selective blockers and manipulated expression levels. Journal of Biological Chemistry 276: 12249-12256. PMID: 11278890.

Wei, S.H., O. Safrina, Y. Yu, K.R. Garrod, M.D. Cahalan, and I. Parker. 2007 Ca2+ signals in CD4+ T cells during early contacts with antigen-bearing dendritic cells in lymph node. Journal of Immunology 179: 1586-1594.

Krummel, M.F. and M.D. Cahalan. 2010. The immunological synapse: a dynamic platform for local signaling. Journal of Clinical Immunology 30: 364-372. PMID: 20390326.

Flach, H., M. Rosenbaum, M. Duchniewicz, S. Kim, S.L. Zhang, M.D. Cahalan, G. Mittler, and R. Grosschedl. 2010. Mzb1 protein regulates calcium homeostasis, antibody secretion, and integrin activation innate-like B cells. Immunity 33: 723-735. PMID: 21093319.

Newton, R.H., S. Leverrier, S. Srikanth, Y. Gwack, M.D. Cahalan, and C.M. Walsh. 2011. Protein kinase D orchestrates the activation of DRAK2 in response to TCR-induced Ca2+ influx and mitochondrial reactive oxygen generation. Journal of Immunology 186: 940-50. PMID: 21148796.

Dong, T.X., S. Othy, M.L Greenberg, A. Jairaman, C. Akunwafo, S. Leverrier, Y. Yu, I. Parker, J.L. Dynes and M.D. Cahalan. 2017. Intermittent Ca2+ signals mediated by Orai1 regulate basal T cell motility. eLife 6:e27827. PMID: 29239723.

Dong, T.X., S. Othy, A. Jairaman, S. Skupsky, A. Zavala, I. Parker, and M.D. Cahalan. 2017. T cell calcium dynamics visualized in a ratiometric tdTomato-GCaMP6f transgenic reporter mouse. eLife 6:e32417. PMID: 29239725.

4. Molecular identification of STIM and Orai proteins that underlie store-operated calcium signaling. Electrophysiological analysis of a tiny, Ca2+ selective current in T cells revealed an unusual ion channel activity that underlies Ca2+ signaling in T cells. The biophysical fingerprint included: a voltage-independent, Ca2+-selective channel that is activated by T cell receptor engagement; inward rectification and very low single-channel conductance; and block by polyvalent cations. Over the next 15 years, heterologous expression of candidate genes failed to replicate the biophysical signature; the molecular identity of CRAC channels, and store-operated Ca2+ channels more generally, remained enigmatic from the late 1980s until 2005. Our Ca2+ indicator-based candidate and genome-wide RNAi screens provided key breakthroughs. We showed that knocking down either STIM or Orai inhibits CRAC channel activity, and that overexpression of both together greatly amplifies CRAC channel activity. By mutagenesis and functional analysis, we identified the molecular mechanism for CRAC channel activation: ER-resident STIM proteins sense the depletion of Ca2+ within the lumen of the ER, translocate to junctions adjacent to the plasma membrane, and promote clustering and opening of Orai1 channels that conduct Ca2+ ions into the cell. These discoveries were highlighted by Science magazine as “Cell Signaling Breakthroughs of the Year” in 2005 and 2006. More recently, we have developed probes that permit Orai1 channel activity to be observed directly, with resolution to the level of single channels.

Yeromin A.V., J. Roos, K.A. Stauderman, and M.D. Cahalan. 2004. A store-operated calcium channel in Drosophila S2 cells. Journal of General Physiology 123:167-182.

Roos, J. DiGregorio, P.J., A.V. Yeromin, K. Ohlsen, M. Lioudyno, S. Zhang, O. Safrina, J.A. Kozak, S. Wagner, M.D. Cahalan, G. Velicelebi, and K.A. Stauderman. 2005. STIM1, an essential and conserved component of store-operated calcium channel function. J Cell Biol 169: 435-445. PMC2171946.

Zhang S.L. Y. Yu, J. Roos, J.A. Kozak, T.J. Deerinck, M.H. Ellisman, K.A. Stauderman, and M.D. Cahalan. 2005. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437: 902-905. PMC1618826.

Zhang, S.L., A.V. Yeromin, X.H-F. Zhang, Y. Yu, O. Safrina, A. Penna, J. Roos, K.A. Stauderman, and M.D. Cahalan. 2006. Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate CRAC channel activity. PNAS 103: 9357-9362. PMC1482614.

Yeromin, A.V., S.L. Zhang, W. Jiang, Y. Yu, O. Safrina, and M.D. Cahalan. 2006. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443:226-229. PMC2756048.

Lioudyno, M.I., J.A. Kozak. A. Penna, O. Safrina, S.L. Zhang, D. Sen, J. Roos, K.A. Stauderman, and M.D. Cahalan. 2008. Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. PNAS 105:2011-2016. PMC2538873.

Penna, A., A. Demuro, A.V. Yeromin, S.L. Zhang, O. Safrina, I. Parker, and M.D. Cahalan. 2008. The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 456: 116-120. PMID: 18820677.

Zhang, S.L., J.A. Kozak, W.Jiang, A.V. Yeromin, J. Chen, Y. Yu, A. Penna, W. Shen, V. Chi, and M.D. Cahalan. 2008. Store-dependent and -independent modes regulating Ca2+ release-activated Ca2+ channel activity of human Orai1 and Orai3. Journal of Biological Chemistry 283: 17662-17671.

Cahalan, M.D. 2009. STIM-ulating store-operated Ca2+ entry. Nature Cell Biology 11: 669-677. PMID: 19488056.

Cahalan, M.D. 2010. How to STIMulate calcium channels. Science 330: 43-44. PMID: 20929798.

Demuro, A., A. Penna, O. Safrina, A.Y. Yeromin, A. Amcheslavsky, M.D. Cahalan, and I. Parker. 2011. Subunit stoichiometry of human Orai1 and Orai3 channels in closed and open states. Proceedings of the National Academy of Sciences U.S.A. 108: 17832-7. PMID: 21987805.

Zhang, S.L., A.V. Yeromin, J. Hu, A. Amcheslavsky, H. Zheng, and M.D. Cahalan. 2011. Mutations in Orai1 TM1 cause STIM1-independent activation of Orai1 channels at glycine 98 and channel closure at arginine 91. Proceedings of the National Academy of Sciences U.S.A. 108: 17838-43. PMID: 21987804.

Khadra, N., L. Bresson-Bepoldin, A. Penna, B. Chaigne-Delalande, B. Segui, T. Levade, A.M. Vacher, J. Reiffers, T. Ducret, J.F. Moreau, M.D. Cahalan, P. Vacher, and P. Legembre. 2011. CD95 triggers Orai1-mediated localized Ca2+ entry, regulates recruitment of protein kinase C (PKC) ß2, and prevents death-inducing signaling complex formation. Proceedings of the National Academy of Sciences U.S.A. 108:19072-7. PMID: 22065776.

Greenberg, M.L., Y. Yu, S. Leverrier, S.L. Zhang, I. Parker, and M.D. Cahalan. 2013. Orai1 function is essential for T cell homing to lymph nodes. Journal of Immunology 190: 3197-3206. PMID 23455504.

Amcheslavsky, A., O. Safrina, and M.D. Cahalan. 2013. Orai3 TM3 point mutation G158C alters kinetics of 2-APB-induced gating by disulfide bridge formation with TM2 C101. Journal of General Physiology 142: 405-412. PMID 24081982.

Amcheslavsky, A., O. Safrina, and M.D. Cahalan. 2014. State-dependent block of Orai3 TM1 and TM3 cysteine mutants: insights into 2-APB activation. Journal of General Physiology 143: 621-631. PMID: 24733836.

Amcheslavsky, A., M.L. Wood, A.V. Yeromin, I. Parker, J.A. Freites, D.J. Tobias, and M.D. Cahalan. 2015. Molecular biophysics of Orai store-operated Ca2+ channels. Biophysical Journal 108: 237-246. PMID: 25606672.

Perni, S., J.L. Dynes, A.V. Yeromin, M.D. Cahalan, and C. Franzini-Armstrong. 2015. Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry. Proceedings of the National Academy of Sciences U.S.A. 112(40): E25533-42. PMID: 26351694.

Dynes, J.L., A. Amcheslavsky, and M.D. Cahalan. 2016. Genetically targeted single-channel optical recording reveals multiple Orai1 gating states and oscillations in calcium influx. Proceedings of the National Academy of Sciences U.S.A. 113: 440-5. PMID: 26712003.

5. Immuno-imaging of cellular dynamics in the immune system. Introduced by our group to the field of immunology, two-photon (2-P) microscopy permits real-time visualization of living cells within lymphoid organs, revealing an elegant cellular choreography. The goal is to determine how cellular behavior shapes immune responses in vivo. I have collaborated since 2001 with Ian Parker in these studies, which have illuminated the cellular dynamics of antigen recognition, lymphocyte priming, differentiation, cellular migration, the action of adjuvants, effects of immunosuppressive drugs, and mechanisms of immunoregulation. 2-P imaging studies have changed the paradigm of how we understand immune responses. Our studies on lymph node cellular dynamics led to an improved understanding of how the lymph node functions as the organ of antigen recognition and activation. More recently, we applied 2-P imaging to immune responses in the periphery and to additional cell types. Motile effector T cells are completely immobilized by immunosuppressive therapy using a Kv1.3 channel blocker in inflamed ear tissue during a delayed type hypersensitivity response. Host NK cells patrol and destroy donor-derived DCs during transplant rejection. We further showed that human T and B cells, like mouse lymphocytes, exhibit robust motility in lymph nodes following engraftment in immunocompromised mice. We extended the scope of 2-P immuno-imaging by developing intravital skin preparations to visualize dermal DCs and Langerhans cells entering afferent lymphatic vessels; a lung preparation to investigate migrations of DCs and CD8+ T cells during influenza infection; and a spinal cord preparation to investigate remyelination induced by oligodendrocytes during neuroinflammation.

Miller, M.M., S.H. Wei, I. Parker, and M.D. Cahalan. 2002. Two-photon imaging of lymphocyte motility and dynamic antigen responses in intact lymph node. Science 296: 1869-1873. PMID: 12016203.

Cahalan, M.D., I. Parker, S.H. Wei, and M.J. Miller. 2002. Two photon tissue imaging: seeing the immune response in a fresh light. Nature Reviews Immunology 2: 872-880. PMID: 12415310.

Miller, M.M., S.H. Wei, I. Parker, and M.D. Cahalan. 2003. Autonomous T cell trafficking examined in vivo using intravital two-photon microscopy. Proceedings of the National Academy of Sciences U.S.A. 100: 2604-2609. PMID: 12601158.

Miller, M.J., A.S. Hejazi, S.H. Wei, I. Parker, and M.D. Cahalan. 2004. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node. Proceedings of the National Academy of Sciences U.S.A. 101: 998-1003. PMID: 14722354.

Miller, M.J., A. Safrina, I. Parker, and M.D. Cahalan. 2004. Imaging the single-cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J. Exp. Med. 200: 847-856. PMC2213293.

Okada, T., M.J. Miller, I. Parker, M.F. Krummel, M. Neighbors, S.B. Hartley, A. O’Garra, M.D. Cahalan, and J.G. Cyster. 2005. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS, Biology 3:1047-061.

Wei, S.H., H. Rosen, M.P. Matheu, M.G. Sanna, S-K. Wang, E. Jo, C-H Wong, I. Parker, and M.D. Cahalan. 2005. S1P1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nature Immunology 6, 1228 - 1235. PMID: 16273098.

Sanna, M.G., S.K. Wang, P.J. Gonzalez-Cabrera, A. Don, D. Marsolais, M.P. Matheu, S.H. Wei, I. Parker, E. Jo, W.C. Cheng, M.D. Cahalan, C.H. Wong, H. Rosen. 2006. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nature Chemical Biology 2:434-441. PMID: 16829954.

Garrod, K.R., S.H. Wei, I. Parker, and M.D. Cahalan. 2007. Natural killer cells actively patrol peripheral lymph nodes forming stable conjugates to eliminate MHC-mismatched targets. Proceedings of the National Academy of Sciences U.S.A. 104: 12081-12086.

Matheu, M.P., J.A. Deane, I. Parker, D.A. Fruman, and M.D. Cahalan. 2007 Class IA phosphoinositide 3-kinase modulates basal lymphocyte motility in the lymph node. Journal of Immunology 179: 2261-2269. PMID: 17675487.

Sen, D., T.J. Deerinck, M.H. Ellisman, I. Parker, and M.D. Cahalan. 2008. Quantum dots for tracking dendritic cells and priming an immune response in vitro and in vivo. PLoS ONE 10.1371/journal.pone.0003290. PMID: 18820727.

Garrod, K.R., F-C. Liu, L.E. Forrest, I. Parker, S-M. Kang, and M.D. Cahalan. 2010. Natural killer cell patrolling and elimination of donor-derived dendritic cells favors indirect alloreactivity. Journal of Immunology 184: 2329-2336. PMID: 20139277.

Sen, D., L. Forrest, T.B. Kepler, I. Parker, M.D. Cahalan. 2010. Selective and site-specific mobilization of dermal dendritic cells and Langerhans cells by Th1- and Th2-polarizing adjuvants. Proceedings of the National Academy of Sciences U.S.A. 107: 8334-9. PMID: 20404167.

Germain, R.N., E.A. Robey, and M.D. Cahalan. 2012. A decade of imaging cellular motility and interaction dynamics in the immune system. Science 33: 1676-81. PMID 22745423.

Matheu, M.P., Y. Su, M.L. Greenberg, C.A. Blanc, I. Parker, D.W. Scott, and M.D. Cahalan. 2012. Toll-like receptor 4-activated B cells out-compete Toll-like receptor 9-activated B cells to establish peripheral immunological tolerance. 2012. Proceedings of the National Academy of Sciences U.S.A. 109:E1258-66. PMID: 22511718.

Matheu, M.P., J.R. Teijaro, K.B. Walsh, M.L. Greenberg, D. Marsolais, I. Parker, H. Rosen, M.B.A. Oldstone, and M.D. Cahalan. 2013. Three phases of CD8 T cell response in the lung following H1N1 influenza infection and sphingosine 1 phosphate agonist therapy. PLoS-ONE 10.1371/journal.pone.0058033. PMID: 23533579.

Greenberg, M.L., J.G. Weinger, M.P. Matheu, K.S. Carbajal, I. Parker, W.B. Macklin, T.E. Lane, and M.D. Cahalan. 2014. Two-photon imaging of remyelination of spinal cord axons by engrafted neural precursor cells in a viral model of multiple sclerosis. PNAS Jun 3;111(22):E2349-55. PMC4050611.

Matheu, M.P., S. Othy, M.L. Greenberg, T.X. Dong, M. Schuijs, K. Deswarte, H. Hammad, B.N. Lambrecht, I. Parker, and M.D. Cahalan. 2015. Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nature Communications 6:6219. doi: 10.1038/ncomms7219. PMC4347855.
NIH RO1 NS14609, "Molecular Mechanisms of Ion Channels in T Lymphocytes". 1978-present.
NIH RO1 GM41514, "Functional Imaging of Lymphocyte Motility and Cell Interactions in Lymph Node". 1984-2014.
NIH R21 AI117555 "A Transgenic Mouse Line to Map Cell-Type Specific Calcium Signals In Vivo." 2015-2017.
NIH RO1 AI121945. "Cellular and Molecular Mechanisms of Regulatory T Cells in EAE." 07/01/16-06/30/21
Professional Societies
Biophysical Society 1973-present. Councilor 2008-2011
Society of General Physiologists member since 1978. Councilor 1993-1995, President 1998, Traveling Scholar Award 2011, Journal of General Physiology Editorial Board 1987-98, Advisory Editor 2002-present
Physiological Reviews Editorial Board 2002-2007
American Association of Immunologists
Graduate Programs
Cellular and Molecular Biosciences

Research Center
Institute for Immunology, Cancer Center
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