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    John Vincent Walsh MD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMicrobiology and Physiological Systems
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-3360
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Overview 
        Narrative

        Academic Background

        B.A., Boston College
        M.D., Harvard Medical School

        Role ofIntracellularCa2+ Stores in Nerve Terminals and Exocytosis

        WalshThe primary focus of this laboratory is on the role of intracellular Ca2+ stores in nerve terminals. It is clear that Ca2+ influx from outside the terminal triggers exocytosis, and this process has been and continues to be the subject of intensive study. In contrast the role of Ca2+ flowing into the cytosol of terminals from intracellular stores is unknown, and the very existence of such stores was in doubt until recently. Using a preparation of freshly isolated nerve terminals from hypothalamic neurons, we have now demonstrated the existence of short-lived, focal, cyotosolic Ca2+transients arising from intraterminal stores. In certain respects these “Ca2+ sparks†found in myocytes, and hence we call these transients resemble “Ca2+ syntillas†from scintilla (L. spark) in a synaptic structure, a nerve terminal. (DeCrescenzo et al, Journal of Neuroscience (2004) 24:1226-1235.)

        The study of Ca2+ syntillas represents an entirely new field of presynaptic physiology, and we are presently examining the function and regulation of the syntillas and the nature of the stores from which they arise. Our work on syntillas reflects both an interest in presynaptic function and in alterations in Ca2+ concentration within subcellular "microdomains." Ca2+ is a signal for an extraordinary number of cellular processes which presents the cell with the problem of undesirable cross-talk among the signaling pathways. One way the cell avoids such cross-talk is to confine Ca2+ signals within microdomains. This we study by using widefield microscopy with high spatial and temporal resolution to follow Ca2+ changes in the cytosol and organelles of living cells with fluorescent Ca2+-sensitive dyes. We employ a unique digital imaging microscope which was developed by the Biomedical Imaging Group in our department in conjunction with Lincoln Laboratories at MIT. We believe this instrument, based on "Star Wars" technology, is the most powerful yet devised for this sort of study. More often than not we use imaging and patch clamping simultaneously.

        Asecond and very recent interest of the laboratory is neurogenesis in the adult and the source and function of neural stem cells.

        We work very closely with the Biomedical Imaging Group whose members include optical physicists, mathematicians and computer scientists. These faculty members are a complement to the biologists and provide us with a highly talented set of collaborators, allowing us to use a genuine multidisciplinary approach.

        Biomedical Imaging Group Home Page



        Rotation Projects

        Potential Rotation Projects

        For all three projects, digital imaging technology will be employed, allowing the student to develop a familiarity with this technology. For the students who are interested, each project can also involve patch-clamp technology allowing a first acquaintance with this technology as well. The areas below are general ones and the exact nature of each student's project will be worked out in the course of a one-on-one discussion.

        1. Study of Ca2+ sparks in cardiac muscle cells.
        2. Study of Ca2+ sparks in airway smooth muscle with an emphasis on the effects of anti-athmatic agents.
        3. Study of Ca2+ microdomains in neuronal terminals.


        Post Docs

        A postdoctoral position is available to study in this laboratory. Contact Dr. Walsh for additional details.

        Bibliographic 
        selected publications
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        1. De Crescenzo V, Fogarty KE, Lefkowitz JJ, Bellve KD, Zvaritch E, Maclennan DH, Walsh JV. Type 1 ryanodine receptor knock-in mutation causing central core disease of skeletal muscle also displays a neuronal phenotype. Proc Natl Acad Sci U S A. 2012 Jan 10; 109(2):610-5.
          View in: PubMed
        2. McNally JM, De Crescenzo V, Fogarty KE, Walsh JV, Lemos JR. Individual calcium syntillas do not trigger spontaneous exocytosis from nerve terminals of the neurohypophysis. J Neurosci. 2009 Nov 11; 29(45):14120-6.
          View in: PubMed
        3. Lefkowitz JJ, Fogarty KE, Lifshitz LM, Bellve KD, Tuft RA, ZhuGe R, Walsh JV, De Crescenzo V. Suppression of Ca2+ syntillas increases spontaneous exocytosis in mouse adrenal chromaffin cells. J Gen Physiol. 2009 Oct; 134(4):267-80.
          View in: PubMed
        4. Mello CC, Walsh JV. The time to demand funding. Science. 2009 Jan 9; 323(5911):208.
          View in: PubMed
        5. De Crescenzo V, Fogarty KE, Zhuge R, Tuft RA, Lifshitz LM, Carmichael J, Bellvé KD, Baker SP, Zissimopoulos S, Lai FA, Lemos JR, Walsh JV. Dihydropyridine receptors and type 1 ryanodine receptors constitute the molecular machinery for voltage-induced Ca2+ release in nerve terminals. J Neurosci. 2006 Jul 19; 26(29):7565-74.
          View in: PubMed
        6. ZhuGe R, DeCrescenzo V, Sorrentino V, Lai FA, Tuft RA, Lifshitz LM, Lemos JR, Smith C, Fogarty KE, Walsh JV. Syntillas release Ca2+ at a site different from the microdomain where exocytosis occurs in mouse chromaffin cells. Biophys J. 2006 Mar 15; 90(6):2027-37.
          View in: PubMed
        7. Zhuge R, Fogarty KE, Baker SP, McCarron JG, Tuft RA, Lifshitz LM, Walsh JV. Ca(2+) spark sites in smooth muscle cells are numerous and differ in number of ryanodine receptors, large-conductance K(+) channels, and coupling ratio between them. Am J Physiol Cell Physiol. 2004 Dec; 287(6):C1577-88.
          View in: PubMed
        8. De Crescenzo V, ZhuGe R, Velázquez-Marrero C, Lifshitz LM, Custer E, Carmichael J, Lai FA, Tuft RA, Fogarty KE, Lemos JR, Walsh JV. Ca2+ syntillas, miniature Ca2+ release events in terminals of hypothalamic neurons, are increased in frequency by depolarization in the absence of Ca2+ influx. J Neurosci. 2004 Feb 4; 24(5):1226-35.
          View in: PubMed
        9. O'Reilly CM, Fogarty KE, Drummond RM, Tuft RA, Walsh JV. Spontaneous mitochondrial depolarizations are independent of SR Ca2+ release. Am J Physiol Cell Physiol. 2004 May; 286(5):C1139-51.
          View in: PubMed
        10. O'Reilly CM, Fogarty KE, Drummond RM, Tuft RA, Walsh JV. Quantitative analysis of spontaneous mitochondrial depolarizations. Biophys J. 2003 Nov; 85(5):3350-7.
          View in: PubMed
        11. Clarke AL, Petrou S, Walsh JV, Singer JJ. Modulation of BK(Ca) channel activity by fatty acids: structural requirements and mechanism of action. Am J Physiol Cell Physiol. 2002 Nov; 283(5):C1441-53.
          View in: PubMed
        12. Clarke AL, Petrou S, Walsh JV, Singer JJ. Site of action of fatty acids and other charged lipids on BKCa channels from arterial smooth muscle cells. Am J Physiol Cell Physiol. 2003 Mar; 284(3):C607-19.
          View in: PubMed
        13. Zhuge R, Fogarty KE, Tuft RA, Walsh JV. Spontaneous transient outward currents arise from microdomains where BK channels are exposed to a mean Ca(2+) concentration on the order of 10 microM during a Ca(2+) spark. J Gen Physiol. 2002 Jul; 120(1):15-27.
          View in: PubMed
        14. Dopico AM, Walsh JV, Singer JJ. Natural bile acids and synthetic analogues modulate large conductance Ca2+-activated K+ (BKCa) channel activity in smooth muscle cells. J Gen Physiol. 2002 Mar; 119(3):251-73.
          View in: PubMed
        15. Kirber MT, Etter EF, Bellve KA, Lifshitz LM, Tuft RA, Fay FS, Walsh JV, Fogarty KE. Relationship of Ca2+ sparks to STOCs studied with 2D and 3D imaging in feline oesophageal smooth muscle cells. J Physiol. 2001 Mar 1; 531(Pt 2):315-27.
          View in: PubMed
        16. ZhuGe R, Fogarty KE, Tuft RA, Lifshitz LM, Sayar K, Walsh JV. Dynamics of signaling between Ca(2+) sparks and Ca(2+)- activated K(+) channels studied with a novel image-based method for direct intracellular measurement of ryanodine receptor Ca(2+) current. J Gen Physiol. 2000 Dec; 116(6):845-64.
          View in: PubMed
        17. Drummond RM, Mix TC, Tuft RA, Walsh JV, Fay FS. Mitochondrial Ca2+ homeostasis during Ca2+ influx and Ca2+ release in gastric myocytes from Bufo marinus. J Physiol. 2000 Feb 1; 522 Pt 3:375-90.
          View in: PubMed
        18. ZhuGe R, Tuft RA, Fogarty KE, Bellve K, Fay FS, Walsh JV. The influence of sarcoplasmic reticulum Ca2+ concentration on Ca2+ sparks and spontaneous transient outward currents in single smooth muscle cells. J Gen Physiol. 1999 Feb; 113(2):215-28.
          View in: PubMed
        19. ZhuGe R, Sims SM, Tuft RA, Fogarty KE, Walsh JV. Ca2+ sparks activate K+ and Cl- channels, resulting in spontaneous transient currents in guinea-pig tracheal myocytes. J Physiol. 1998 Dec 15; 513 ( Pt 3):711-8.
          View in: PubMed
        20. McCarron JG, McGeown JG, Walsh JV, Fay FS. Modulation of high- and low-voltage-activated calcium currents in smooth muscle by calcium. Am J Physiol. 1997 Sep; 273(3 Pt 1):C883-92.
          View in: PubMed
        21. Petrou S, Ugur M, Drummond RM, Singer JJ, Walsh JV. P2X7 purinoceptor expression in Xenopus oocytes is not sufficient to produce a pore-forming P2Z-like phenotype. FEBS Lett. 1997 Jul 14; 411(2-3):339-45.
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        22. Ugur M, Drummond RM, Zou H, Sheng P, Singer JJ, Walsh JV. An ATP-gated cation channel with some P2Z-like characteristics in gastric smooth muscle cells of toad. J Physiol. 1997 Jan 15; 498 ( Pt 2):427-42.
          View in: PubMed
        23. Ordway RW, Petrou S, Kirber MT, Walsh JV, Singer JJ. Stretch activation of a toad smooth muscle K+ channel may be mediated by fatty acids. J Physiol. 1995 Apr 15; 484 ( Pt 2):331-7.
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        24. Petrou S, Ordway RW, Kirber MT, Dopico AM, Hamilton JA, Walsh JV, Singer JJ. Direct effects of fatty acids and other charged lipids on ion channel activity in smooth muscle cells. Prostaglandins Leukot Essent Fatty Acids. 1995 Feb-Mar; 52(2-3):173-8.
          View in: PubMed
        25. Petrou S, Ordway RW, Hamilton JA, Walsh JV, Singer JJ. Structural requirements for charged lipid molecules to directly increase or suppress K+ channel activity in smooth muscle cells. Effects of fatty acids, lysophosphatidate, acyl coenzyme A and sphingosine. J Gen Physiol. 1994 Mar; 103(3):471-86.
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        26. McCarron JG, Walsh JV, Fay FS. Sodium/calcium exchange regulates cytoplasmic calcium in smooth muscle. Pflugers Arch. 1994 Feb; 426(3-4):199-205.
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        27. Dopico AM, Kirber MT, Singer JJ, Walsh JV. Membrane stretch directly activates large conductance Ca(2+)-activated K+ channels in mesenteric artery smooth muscle cells. Am J Hypertens. 1994 Jan; 7(1):82-9.
          View in: PubMed
        28. Petrou S, Ordway RW, Singer JJ, Walsh JV. A putative fatty acid-binding domain of the NMDA receptor. Trends Biochem Sci. 1993 Feb; 18(2):41-2.
          View in: PubMed
        29. Hisada T, Singer JJ, Walsh JV. Aluminofluoride activates hyperpolarization- and stretch-activated cationic channels in single smooth muscle cells. Pflugers Arch. 1993 Jan; 422(4):397-400.
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        30. Hisada T, Walsh JV, Singer JJ. Stretch-inactivated cationic channels in single smooth muscle cells. Pflugers Arch. 1993 Jan; 422(4):393-6.
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        31. Clapp LH, Sims SM, Singer JJ, Walsh JV. Role for diacylglycerol in mediating the actions of ACh on M-current in gastric smooth muscle cells. Am J Physiol. 1992 Dec; 263(6 Pt 1):C1274-81.
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        32. McCarron JG, McGeown JG, Reardon S, Ikebe M, Fay FS, Walsh JV. Calcium-dependent enhancement of calcium current in smooth muscle by calmodulin-dependent protein kinase II. Nature. 1992 May 7; 357(6373):74-7.
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        33. Kirber MT, Ordway RW, Clapp LH, Walsh JV, Singer JJ. Both membrane stretch and fatty acids directly activate large conductance Ca(2+)-activated K+ channels in vascular smooth muscle cells. FEBS Lett. 1992 Feb 3; 297(1-2):24-8.
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        34. Vivaudou MB, Singer JJ, Walsh JV. Multiple types of Ca2+ channels in visceral smooth muscle cells. Pflugers Arch. 1991 Mar; 418(1-2):144-52.
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        35. Ordway RW, Singer JJ, Walsh JV. Direct regulation of ion channels by fatty acids. Trends Neurosci. 1991 Mar; 14(3):96-100.
          View in: PubMed
        36. Hisada T, Ordway RW, Kirber MT, Singer JJ, Walsh JV. Hyperpolarization-activated cationic channels in smooth muscle cells are stretch sensitive. Pflugers Arch. 1991 Jan; 417(5):493-9.
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        37. Sims SM, Clapp LH, Walsh JV, Singer JJ. Dual regulation of M current in gastric smooth muscle cells: beta-adrenergic-muscarinic antagonism. Pflugers Arch. 1990 Nov; 417(3):291-302.
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        38. Sims SM, Vivaudou MB, Hillemeier C, Biancani P, Walsh JV, Singer JJ. Membrane currents and cholinergic regulation of K+ current in esophageal smooth muscle cells. Am J Physiol. 1990 May; 258(5 Pt 1):G794-802.
          View in: PubMed
        39. Kirber MT, Ordway RW, Clapp LH, Sims SM, Walsh JV, Singer JJ. Voltage, ligand, and mechanically gated channels in freshly dissociated single smooth muscle cells. Prog Clin Biol Res. 1990; 334:123-43.
          View in: PubMed
        40. Ordway RW, Walsh JV, Singer JJ. Arachidonic acid and other fatty acids directly activate potassium channels in smooth muscle cells. Science. 1989 Jun 9; 244(4909):1176-9.
          View in: PubMed
        41. Becker PL, Singer JJ, Walsh JV, Fay FS. Regulation of calcium concentration in voltage-clamped smooth muscle cells. Science. 1989 Apr 14; 244(4901):211-4.
          View in: PubMed
        42. Clapp LH, Vivaudou MB, Singer JJ, Walsh JV. Substance P, like acetylcholine, augments one type of Ca2+ current in isolated smooth muscle cells. Pflugers Arch. 1989 Mar; 413(5):565-7.
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        43. Kirber MT, Walsh JV, Singer JJ. Stretch-activated ion channels in smooth muscle: a mechanism for the initiation of stretch-induced contraction. Pflugers Arch. 1988 Sep; 412(4):339-45.
          View in: PubMed
        44. Vivaudou MB, Clapp LH, Walsh JV, Singer JJ. Regulation of one type of Ca2+ current in smooth muscle cells by diacylglycerol and acetylcholine. FASEB J. 1988 Jun; 2(9):2497-504.
          View in: PubMed
        45. Sims SM, Singer JJ, Walsh JV. Antagonistic adrenergic-muscarinic regulation of M current in smooth muscle cells. Science. 1988 Jan 8; 239(4836):190-3.
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        46. Sims SM, Vivaudou MB, Clapp LH, Lassignal NL, Walsh JV, Singer JJ. Neurotransmitter regulation of ionic channels in freshly dissociated smooth muscle cells. Ann N Y Acad Sci. 1988; 527:346-59.
          View in: PubMed
        47. Lieberman M, Hauschka SD, Hall ZW, Eisenberg BR, Horn R, Walsh JV, Tsien RW, Jones AW, Walker JL, Poenie M, et al. Isolated muscle cells as a physiological model. Am J Physiol. 1987 Sep; 253(3 Pt 1):C349-63.
          View in: PubMed
        48. Clapp LH, Vivaudou MB, Walsh JV, Singer JJ. Acetylcholine increases voltage-activated Ca2+ current in freshly dissociated smooth muscle cells. Proc Natl Acad Sci U S A. 1987 Apr; 84(7):2092-6.
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        49. Walsh JV, Singer JJ. Identification and characterization of major ionic currents in isolated smooth muscle cells using the voltage-clamp technique. Pflugers Arch. 1987 Feb; 408(2):83-97.
          View in: PubMed
        50. Singer JJ, Walsh JV. Characterization of calcium-activated potassium channels in single smooth muscle cells using the patch-clamp technique. Pflugers Arch. 1987 Feb; 408(2):98-111.
          View in: PubMed
        51. Sims SM, Walsh JV, Singer JJ. Substance P and acetylcholine both suppress the same K+ current in dissociated smooth muscle cells. Am J Physiol. 1986 Oct; 251(4 Pt 1):C580-7.
          View in: PubMed
        52. Vivaudou MB, Singer JJ, Walsh JV. An automated technique for analysis of current transitions in multilevel single-channel recordings. Pflugers Arch. 1986 Oct; 407(4):355-64.
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        53. Lassignal NL, Singer JJ, Walsh JV. Multiple neuropeptides exert a direct effect on the same isolated single smooth muscle cell. Am J Physiol. 1986 May; 250(5 Pt 1):C792-8.
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        54. Singer JJ, Walsh JV. Large-conductance Ca2+-activated K+ channels in freshly dissociated smooth muscle cells. Membr Biochem. 1986; 6(2):83-110.
          View in: PubMed
        55. Sims SM, Singer JJ, Walsh JV. Cholinergic agonists suppress a potassium current in freshly dissociated smooth muscle cells of the toad. J Physiol. 1985 Oct; 367:503-29.
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        56. Kirber MT, Singer JJ, Walsh JV, Fuller MS, Peura RA. Possible forms for dwell-time histograms from single-channel current records. J Theor Biol. 1985 Sep 7; 116(1):111-26.
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        57. Singer JJ, Walsh JV. Large conductance ca-activated k channels in smooth muscle cell membrane: reduction in unitary currents due to internal na ions. Biophys J. 1984 Jan; 45(1):68-70.
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        58. Walsh JV, Singer JJ. Ca++-activated K+ channels in vertebrate smooth muscle cells. Cell Calcium. 1983 Dec; 4(5-6):321-30.
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        59. Walsh JV, Singer JJ. Voltage clamp of single freshly dissociated smooth muscle cells: current-voltage relationships for three currents. Pflugers Arch. 1981 May; 390(2):207-10.
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        60. Walsh JV, Singer JJ. Penetration-induced hyperpolarization as evidence for Ca2+ activation of K+ conductance in isolated smooth muscle cells. Am J Physiol. 1980 Nov; 239(5):C182-9.
          View in: PubMed
        61. Walsh JV, Singer JJ. Calcium action potentials in single freshly isolated smooth muscle cells. Am J Physiol. 1980 Nov; 239(5):C162-74.
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        62. Singer JJ, Walsh JV. Rectifying properties of the membrane of single freshly isolated smooth muscle cells. Am J Physiol. 1980 Nov; 239(5):C175-81.
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        63. Singer JJ, Walsh JV. Passive properties of the membrane of single freshly isolated smooth muscle cells. Am J Physiol. 1980 Nov; 239(5):C153-61.
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        64. Walsh JV, Houk JC, Mugnaini E. Identification of unitary potentials in turtle cerebellum and correlations with structures in granular layer. J Neurophysiol. 1974 Jan; 37(1):30-47.
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