Joshua Singer, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Physiology

Other Affiliation(s):
   Biochemistry and Molecular Pharmacology
   Program in Neuroscience

Ion channel behavior and cellular physiological and biochemical processes

The aim of our research is to understand the molecular mechanisms involved in membrane electrical events and the relationship of these events to biochemical and physiological processes. Studies are carried out using mammalian and amphibian single smooth muscle cells and other cell types as well as various expression systems including Xenopus oocytes. We are using voltage-clamp techniques for measuring macroscopic membrane currents, the patch-clamp technique for measuring currents passing through single ion channels, Ca²⁺ imaging techniques for examining the temporal and spatial distribution of cellular Ca²⁺, and molecular biological techniques for studying cloned channels, identifying new channels, and determining various functional domains of channel proteins. We have been examining the voltage, chemical, mechanical, and ionic control of membrane channels; the mechanism of action of neurotransmitters, peptides, drugs and other agents; and the role of these in cellular function. Specifically, we have recently been interested in the direct effects of fatty acids, sphingosine, steroids, and other biologically active lipids on smooth muscle and neuron ion channel activity; the role of mechanically-gated ion channels in the control of stretch-induced contraction of smooth muscle; various Ca²⁺ permeable nonselective cation channels activated by caffeine, NMDA and ATP; and the relationship between ion channel gating and changes in the local concentration of cellular Ca²⁺.

Representative Publications

Ordway, R.W., J.V. Walsh, Jr., and J.J. Singer.  Arachidonic acid and other fatty acids directly activate potassium channels in smooth muscle cells.  Science 244: 1176-1179, 1989. [link to PubMed abstract][Link to Journal Article]

Kirber, M.T., R.W. Ordway, L.H. Clapp, J.V. Walsh, Jr., and J.J. Singer.  Both membrane stretch and fatty acids directly activate large conductance Ca²⁺-activated K⁺ channels in vascular smooth muscle cells.  FEBS Letters 297: 24-28, 1992. [link to PubMed abstract] [Link to Journal Article]

Petrou, S., R.W. Ordway, J.A. Hamilton, J.V. Walsh, Jr., and J.J. Singer.  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.  Journal of General Physiology 103: 471-486, 1994 [link to Journal Article]

Guerrero, A., F.S. Fay, and J.J. Singer.  Caffeine activates a Ca²⁺ permeable, non-selective cation channel in smooth muscle cells.  Journal of General Physiology 104: 375-394, 1994. [link to Journal Article]

Guerrero, A., J.J. Singer, and F.S. Fay.  Simultaneous measurement of Ca²⁺ release and influx into smooth muscle cells in response to caffeine:  A novel approach for calculating the fraction of current carried by calcium.  Journal of General Physiology 104: 395-422, 1994. [link to Journal Article]

Petrou, S., R.W. Ordway, M.T. Kirber, A.M. Dopico, J.A. Hamilton, J.V. Walsh Jr., and J.J. Singer.  Direct effects of fatty acids and other charged lipids on ion channel activity in smooth muscle cells.  Prostaglandins Leukotrienes and Essential Fatty Acids 52: 173-178, 1995.  [link to PubMed abstract ][link to Journal Article  ]

Ordway R.W., S. Petrou, M.T. Kirber, J.V. Walsh, Jr., and J.J. Singer.  Stretch activation of a toad smooth muscle K⁺ channel may be mediated by fatty acids.  Journal of Physiology 484: 331-337, 1995. [link to PubMed abstract]

Ugur, M., R.M. Drummond, H. Zou, P. Sheng, J.J. Singer, and J.V. Walsh, Jr.  An ATP-gated cation channel with some P2Z-like characteristics in gastric smooth muscle cells of toad.  Journal of Physiology 498: 427-442, 1997.  [link to PubMed abstract]

Zou, H., L.M. Lifshitz, R.A. Tuft, K.E. Fogarty, and J.J. Singer.  Imaging Ca²⁺ entering the cytoplasm through a single opening of a plasma membrane cation channel.  Journal of General Physiology 114: 575-588, 1999. [link to Journal Article]

Kirber, M.T., A. Guerrero-Hernandez, D.S. Bowman, K.E. Fogarty, R.A. Tuft, J.J. Singer, F.S. Fay.  Multiple pathways responsible for the stretch-induced increase in Ca²⁺ concentration in toad stomach smooth muscle cells.  Journal of Physiology, 524: 3-17, 2000. [link to Journal Article]

Zou, H., M. Ugur, R.M. Drummond, and J.J. Singer. Coupling of a P2Z-like purinoceptor to a fatty acid activated K⁺ channel in toad gastric smooth muscle cells. Journal of Physiology 534: 59-70, 2001. [link to Journal Article]

Dopico, A.M., J.V. Walsh, Jr., and J.J. Singer. Natural bile acids and synthetic analogues modulate large conductance Ca²⁺-activated K⁺ (BK_Ca) channel activity in smooth muscle cells. Journal of General Physiology 119: 251-273, 2002. [link to Journal Article]

Zou, H., L.M. Lifshitz, R.A. Tuft, K.E. Fogarty, and J.J. Singer. Visualization of Ca²⁺ entry through single stretch-activated cation channels. Proceedings of the National Academy of Sciences 99: 6404-6409, 2002.  [link to Journal Article]

Clarke, A.L., S. Petrou, J.V. Walsh, Jr., and J.J. Singer. Modulation of BK_Ca channel activity by fatty acids: structural requirements and mechanism of action. American Journal of Physiology - Cell Physiology 283: C1441-C1453, 2002.  [Link to Journal Article ] 

Clarke, A.L., S. Petrou, J.V. Walsh, Jr., and J.J. Singer. Site of action of fatty acids and other charged lipids on BK_Ca channels from arterial smooth muscle cells. American Journal of Physiology - Cell Physiology 284: C607-C619, 2003.    [Link to Journal Article ]  

Zou, H., L.M. Lifshitz, R.A. Tuft, K.E. Fogarty, and J.J. Singer. Imaging calcium entering the cytosol through a single opening of plasma membrane ion channels: SCCaFTs - fundamental calcium events. Cell Calcium 35: 23-533, 2004.  [Link to Journal Article ]    

Zou, H., L.M. Lifshitz, R.A. Tuft, K.E. Fogarty, and J.J. Singer. Using total fluorescence increase (signal mass) to determine the Ca²⁺ current underlying localized Ca²⁺ events. Journal of General Physiology 124: 259-272, 2004. [Link to Journal Article ]     

Zhang, Y., R.A. Tuft, L.M. Lifshitz, K.E. Fogarty, J.J. Singer, and H. Zou.  Caffeine-activated, large-conductance plasma membrane cation channels in cardiac myocytes: characteristics and significance.  American Journal of Physiology - Heart and Circulatory Physiology 293: H2448-H2461, 2007.   [ Link to Journal Article ]

Academic Background

1966, S.B., S.M., E.E., Massachusetts Institute of Technology
1970, Ph.D., Harvard University

Office: S4-121
Phone: 508-856-6694
E-mail: Joshua.Singer@umassmed.edu

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