Research Summary

Extra- and intracellular pH (pHo and pHi) are important physiological variables that both reflect and, in turn, influence neuronal function. Nevertheless, in comparison with other cell types, the effects of changes in pHo and pHi on neuronal activity remain relatively poorly documented. Also in contrast to non-neuronal cells, where pHi regulating mechanisms constitute a physiologically-important transmembrane signaling pathway, relatively little is known about the mechanisms that act to control pHi in mammalian central neurons. This is surprising because pHi regulating mechanisms regulate not only [H+]i and [HCO3-]i; they also affect [Na+]i, [Cl-]i and the pH in the microenvironment of cells, all of which are of critical importance to neuronal function under physiological and pathophysiological conditions. In light of this background, our research is focuses on the mechanisms that regulate neuronal pHi and their relationships to disease, in particular stroke.

Recent work includes:

a) studying the effects of changes in both extra- and intracellular pH on mammalian central neuronal excitability.

b) characterizing the mechanisms responsible for the regulation of pHi in mammalian central neurons and investigating how the activities of these mechanisms can be regulated by neurotransmitters and intracellular second messenger systems.

c) investigating the effects of anoxia and ischemia on the activities of neuronal pHi regulating mechanisms, especially Na+/H+ exchangers. We are also investigating the relationships between anoxia- and ischemia-induced changes in pHi, [Na+]i and [Ca2+]i in mammalian central neurons, and assessing the contribution of alterations in the activities of pHi regulating mechanisms to these changes.

In addition, in non-neuronal cell types it is well established that Na+/H+ exchangers play a permissive role in migration and growth. We are now actively investigating whether Na+/H+ exchangers play analogous roles in neurons.

Our studies utilize electrophysiological recording techniques and imaging techniques to estimate the intracellular concentrations of Ca2+, H+ and Na+ ions, either singly or in combination, and assess the effects of pHi regulating mechanisms on cytoskeletal events at the growth cone.

Bio

BSc (Bristol)
MD (Bristol)
PhD (London)
Fellow of the Royal College of Anaesthetists (FRCA)
Director, Graduate Program in Cell and Developmental Biology, College for Interdisciplinary Studies

Publications

 
Comprehensive List
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Selected publications

  1. Church, J. & McLennan, H. (1989). Electrophysiological properties of rat CA1 pyramidal neurones in vitro modified by changes in extracellular bicarbonate. J. Physiol. 415, 85-108.
  2. Church, J. & Baimbridge, K.G. (1991). Exposure to high pH medium increases the incidence and extent of dye coupling between rat hippocampal CA1 pyramidal neurons in vitro. J. Neurosci. 11, 3289-3295.
  3. Church, J. (1992). A change from HCO3-/CO2- to HEPES-buffered medium modifies membrane properties of rat CA1 pyramidal neurones in vitro. J. Physiol. 455, 51-71.
  4. Baxter, K.A. & Church, J. (1996). Characterization of acid extrusion mechanisms in cultured fetal rat hippocampal neurones. J. Physiol. 493, 457-470.
  5. Church, J., Baxter, K.A. & McLarnon, J.G. (1998). pH modulation of Ca2+ responses and a Ca2+-dependent K+ channel in cultured rat hippocampal neurones. J. Physiol. 511, 119-132.
  6. Smith, G.A.M., Brett, C.L. & Church, J. (1998). Effects of noradrenaline on intracellular pH in acutely dissociated adult rat hippocampal CA1 neurones. J. Physiol. 512, 487-505.
  7. Thurgur, C. & Church, J. (1998). The anticonvulsant actions of sigma ligands in the Mg2+-free model of epileptiform activity in rat hippocampal slices. Br. J. Pharmacol. 124, 917-929.
  8. Church, J. (1999) Effects of pH changes on calcium-mediated potentials in rat hippocampal neurons in vitro. Neuroscience 89, 731-742.
  9. Diarra, A., Sheldon, C., Brett, C.L., Baimbridge, K.G. & Church, J. (1999). Anoxia-evoked intracellular pH and Ca2+ concentration changes in cultured postnatal rat hippocampal neurons. Neuroscience 93, 1003-1016.
  10. Diarra, A., Sheldon, C., & Church, J. (2001). In situ calibration and [H+] sensitivity of the fluorescent Na+ indicator SBFI. Am. J. Physiol. 280, C1623-C1633.
  11. Sheldon, C. & Church, J. (2002). Intracellular pH response to anoxia in acutely dissociated adult rat hippocampal CA1 neurons. J. Neurophysiol. 87, 2209-2224.
  12. Brett, C.L., Kelly, T., Sheldon, C. & Church, J. (2002). Regulation of Cl–HCO3- exchangers by cAMP-dependent protein kinase in adult rat hippocampal CA1 neurons. J. Physiol. 545, 837-853.
  13. Kelly, T. & Church, J. (2004). pH modulation of currents that contribute to the medium and slow afterhyperpolarizations in rat CA1 pyramidal neurones. J. Physiol. 554, 449-466.
  14. Sheldon, C. & Church, J. (2004). Reduced contribution from Na+/H+ exchange to acid extrusion during anoxia in adult rat hippocampal CA1 neurons. J. Neurochem. 88, 594-603.
  15. Sheldon, C., Cheng, Y.M. & Church, J. (2004). Concurrent measurements of the free cytosolic concentrations of H+ and Na+ ions with fluorescent indicators. Pflügers Arch. – Eur. J. Physiol. 449, 307-318.
  16. Sheldon, C., Diarra, A., Cheng, Y.M. & Church, J. (2004). Sodium influx pathways during and after anoxia in rat hippocampal neurons. J. Neurosci. 24, 11057-11069.
  17. Kelly, T. & Church, J. (2005). The weak bases NH3 and trimethylamine inhibit the medium and slow afterhyperpolarizations in rat CA1 pyramidal neurons. Pflügers Arch. – Eur. J. Physiol. 451, 418-427.
  18. Kelly, T. & Church, J. (2006). Relationships between intracellular calcium and pH in the regulation of the slow afterhyperpolarization in rat hippocampal neurons. J. Neurophysiol. 96, 2342-2353.
  19. Kelly, T., Mann, M. & Church, J. (2007). The slow afterhyperpolarization modulates high pH-induced changes in the excitability of rat CA1 pyramidal neurons. Eur. J. Neurosci. 26, 2844-2856.
  20. Fernandes, H.B., Baimbridge, K.G., Church, J., Hayden, M.R. & Raymond, L.A. (2007). Mitochondrial sensitivity and altered calcium handling underlie enhanced NMDA-induced apoptosis in YAC128 model of Huntington’s disease. J. Neurosci. 27, 13614-13623.
  21. To, K.C.W., Church, J. and O’Connor, T.P. (2007). Combined activation of calpain and calcineurin during ligand-induced growth cone collapse. Mol. Cell. Neurosci. 36, 425-434.
  22. Cheng, Y.M., Kelly, T. & Church, J. (2008). Potential contribution of a voltage-activated proton conductance to acid extrusion from rat hippocampal neurons. Neuroscience 151, 1084-1098.
  23. Ozog, M.A., Modha, G., Church, J., Slotwinska, D and Naus, C.C. (2008). Co-administration of CNTF with its soluble receptor protects against neuronal death and enhances neurite outgrowth. J. Biol. Chem. 283, 6546-6560.
  24. To, K.C.W., Church, J. & O’Connor, T.P. (2008). Growth cone collapse stimulated by both calpain- and Rho-mediated pathways. Neuroscience 153, 645-653.
  25. Diering, G.H., Church, J. and Numata, M. (2009). Secretory carrier membrane protein 2 (SCAMP2) regulates cell-surface targeting of brain-enriched Na+/H+ exchanger NHE5. J. Biol. Chem. 284, 13892-13903.
  26. Sin, W.-C., Moniz, D.M., Ozog, M.A., Tyler, J.E., Numata, M. and Church, J. (2009). Regulation of early neurite morphogenesis by the Na+/H+ exchanger NHE1. J. Neurosci. 29, 8946-8959.
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