Martyn Mahaut-Smith

Personal Details

Professor of Cellular Physiology

Department: Molecular and Cell Biology 
Telephone: 0116 229 7135 
Emailmpms1@le.ac.uk
Postal Address: Henry Wellcome Building, Lancaster Rd, Leicester, LE1 7RH
Web Links:

Biography

My research career in Physiology and Pharmacology started with a PhD on voltage-gated ion channels (1983-86) under the supervision of Dr Robert Meech at the University of Bristol. This was followed by Post-Doc positions in Toronto (lymphocyte ion channels, with Dr Lyanne Schlichter), Cambridge (platelet ion channels, with Drs Tim Rink and Stewart Sage) and San Diego (calcium and cyclic nucleotide signalling, with Prof Roger Tsien). In 1992, I returned to Cambridge, funded initially by a British Heart Foundation Lectureship to continue work on platelet ion channels and calcium signalling. During this time I became fascinated by megakaryocyte function. In 2007 I moved to a Chair in Cellular Physiology at the University of Leicester. My long-standing interest in using state of the art techniques to study biological systems led to an appointment as Academic Head of Core Biotechnology Services (2015-2018) alongside teaching and research activities. In addition, as current Chair of the Disability Equality Action Group, I advocate for improved support for disabled University staff.

Qualifications

  • BSc Hons Physiology, University of Sheffield
  • MA, University of Cambridge
  • PhD, University of Bristol
  • Senior Fellow, Higher Education Academy

Teaching

I teach Physiology and Pharmacology across all years of the Biological Sciences BSc course with a focus on understanding the role of ion channels and intracellular Ca2+ signalling in the cardiovascular system. I have a particular interest in the pedagogy of third year research projects, having been the departmental and College of Life Sciences BSc project Coordinator throughout 2009-2015. I also teach masterclasses on Ca2+ signalling.

Publications (Since 2003)

Articles

  1. Ilkan, Z., Watson, S., Watson, S,P. & Mahaut-Smith, M.P. (2017). P2X1 receptors amplify FcγRIIa- induced calcium entry and functional responses in human platelets. Thrombosis & Haemostasis. 118:369–380
  2. Pugh, N., Maddox, B.D., Bihan, D., Taylor, K.A., Mahaut-Smith, M.P. & Farndale, R.W. (2017). Differential integrin activity mediated by platelet collagen receptor engagement under flow conditions. Thromb.Haemost. 117:1588-1600
  3. Ilkan Z., Wright JR, Goodall A.H., Gibbins J.M., Jones C.I. & Mahaut-Smith M.P. (2017). Evidence for shear- mediated Ca2+ entry through mechanosensitive cation channels in human platelets and a megakaryocytic cell line. J.Biol.Chem. 292:9204-9217.
  4. Lörinczi, E., Helliwell, M., Finch, A., Stansfeld, P.J., Davies, N.W., Mahaut-Smith, M., Muskett, F.W., & Mitcheson, J.S. (2016). Calmodulin regulates Human Ether a Go-Go 1 (hEAG1) potassium channels through interactions of the Eag domain with the cyclic nucleotide binding homology domain. J.Biol.Chem. 291:17907-18.
  5. Wright, J.R. Amisten, S., Goodall, A.H. & Mahaut-Smith, M.P. (2016). Transcriptomic analysis of the ion channelome of human platelets and megakaryocytic cell lines. Thrombosis and Haemostasis, 116(2):272-84.
  6. Wright, A., Mahaut-Smith, M., Symon, F., Sylvius, N., Ran, S., Bafadhel, M., Muessel, M., Bradding, P., Wardlaw, A. & Vial, C. (2016). Impaired P2X1 receptor-mediated adhesion In eosinophils from asthmatic patients. J.Immunol, 196(12):4877-84.
  7. Osman S., Taylor, K.A., Allcock, N., Rainbow, R.D. & Mahaut-Smith, M.P. (2016). Detachment of surface membrane invagination systems by cationic amphiphilic drugs. Scientific Reports 6:18536.
  8. Rinne, A., Mobarec, J.C., Mahaut-Smith, M., Kolb, P. & Bünemann, M. (2015). The mode of agonist binding to a G protein-coupled receptor switches the effect that voltage changes have on signaling. Science Signaling 8, ra110.
  9. Jones, S., Evans, R.J. & Mahaut-Smith, M.P. (2014) Ca2+ influx through P2X1 receptors amplifies P2Y1 receptor-evoked Ca2+ signaling and ADP-evoked platelet aggregation. Molecular Pharmacology 86:243-51
  10. Taylor, K.A., Wright, J.R., Vial, C., Evans, R.J. & Mahaut-Smith, M.P. (2014). Amplification of human platelet activation by surface pannexin-1 channels. Journal of Thrombosis & Haemostasis. 12:987-98.
  11. Vaiyapuri, S., Moraes, L.A., Sage, T., Ali, M.S., Lewis, K.R., Mahaut-Smith, M.P., Oviedo-Orta, E., Simon, A.S., & Gibbins, J.M. (2013). Connexin40 regulates platelet function. Nature Communications 4:2564.
  12. Vaiyapuri, S., Jones, C.I., Sasikumar, P.. Moraes, L.A., Munger, S.J., Wright, J.R., Ali, M.S., Sage, T., Kaiser, W.J., Tucker, K.L., Stain, C.J., Bye, A.P., Jones, S., Oviedo-Orta, E., Simon, A.S., Mahaut-Smith, M.P., & Gibbins, J.M. (2012). Gap Junctions and Connexin Hemichannels Underpin Haemostasis and Thrombosis. Circulation 125, 2479-2491.
  13. Markovic, D., Holdich, J., Al-Sabah, S., Mistry, R., Krasel, C. Mahaut-Smith, M.P.*, Challiss, R.A.J.* (*co-authors of correspondence). (2012). FRET-based detection of M1 muscarinic acetylcholine receptor activation by orthosteric and allosteric agonists. PloS One, 7(1)
  14. Tolhurst, G., Carter, R.N., Miller, N. & Mahaut-Smith, M.P. (2012). Purification of native bone marrow megakaryocytes for studies of gene expression. Methods Mol. Biol. 788, 259-273
  15. Lalo, U., Jones, S., Roberts, J., Mahaut-Smith, M.P. & Evans, R.J. (2012). Heat shock protein 90 regulates trafficking of ATP-gated P2X1 receptors and human platelet responsiveness. Journal of Biological Chemistry, 287:32747-54
  16. Fung, C.Y.E, Jones, S., Ntrakwah, A., Naseem, K.M. Farndale, R.W. & Mahaut-Smith,M.P. (2012). Platelet Ca2+responses coupled to glycoprotein VI and Toll-like receptors persist in the presence of endothelial-derived inhibitors. Blood 119, 3613-3621.
  17. Jones, S., Evans, R.J. & Mahaut-Smith, M.P. (2011). Extracellular Ca2+ modulates ADP-evoked aggregation through altered agonist degradation: implications for conditions used to study P2Y receptor activation. British Journal of Haematology, 153, 83-91.
  18. McCloskey, C., Jones, S., Amisten, S., Snowden, R.T., Kaczmarek, L.K., Erlinge, D., Goodall, A.H., Forsythe, I.D. & Mahaut-Smith, M.P. (2010). Kv1.3 is the exclusive voltage-gated K+ channel of platelets and megakaryocytes : roles in membrane potential, Ca2+ signalling and platelet count. Journal of Physiology, 588:1399-406
  19. Martinez-Pinna, J., Gurung, I.S., Mahaut-Smith, M.P. & Morales, A. (2010). Direct voltage control of endogenous lysophosphatidic acid G-protein-coupled receptors in Xenopus oocytes. Journal of Physiology, 588:1683-93.
  20. Qiu, M.R., Jiang, L., Matthaei, K.I., Schoenwaelder, S., Kuffner, T., Mangin, P., Joseph, J.E., Low, J., Connor, D., Valenzuela, S.M., Curmi, P.M., Brown, L.J., Mahaut-Smith, M., Jackson, S. & Breit, S.N. (2010). Generation and characterisation of mice with null mutation of the chloride intracellular channel 1 gene. Genesis 2010 48:127-36.
  21. Lalo, U., Allsop, R., Mahaut-Smith, M.P. & Evans, R.J. (2010). P2X1 receptor mobility and trafficking; regulation by receptor insertion and activation. Journal of Neurochemistry, 113:1177-87
  22. Gurung, I.S., Martinez-Pinna, J. & Mahaut-Smith, M.P. (2008). Novel consequences of voltage-dependence to G-protein-coupled P2Y1 receptors. British Journal of Pharmacology. 154: 882-9
  23. Tolhurst, G., Carter, R.N., Amisten, S., Holdich, J.P., Erlinge, D. & Mahaut-Smith, M.P. (2008). Expression profiling and electrophysiological studies suggest a major role for Orai1 in the store-operated Ca2+ influx pathway of platelets and megakaryocytes. Platelets 19: 308-13
  24. Killeen, M.J., Thomas, G., Gurung, I.S., Goddard, C.A., Fraser, J.A. Mahaut-Smith, M.P., Colledge, W.H., Grace, A.A. & Huang, C.L. (2007). Arrhythmogenic mechanisms in the isolated perfused hypokalaemic murine heart. Acta Physiol (Oxf). 189: 33-46.
  25. Thomas, G., Gurung, I.S., Killeen, P., Goddard, C.A., Mahaut-Smith, M.P., Colledge, W.H., Grace, A.A. & Huang, C.L. (2007). Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3. Journal of Physiology 578: 85-97.
  26. Fung, C.Y.E, Cendana, C., Farndale, R.W. & Mahaut-Smith, M.P. (2007). Primary and secondary agonists can use P2X1 receptors as a major pathway to increase intracellular Ca2+ in the human platelet. Journal of Thrombosis & Haemostasis. 5: 910-7
  27. Vandenberg, J.I., Varghese, T., Lu, Y., Bursill, J.A., Mahaut-Smith, M.P. & Huang, C.L.H. (2006). Temperature dependence of Human ether-a-go-go Related Gene (HERG) K+ currents. Am J Physiol Cell Physiol. 291, C165-75.
  28. Vial,C., Fung, C.Y.E, Goodall, A.G., Mahaut-Smith, M.P. & Evans, R.J. (2006). Differential sensitivity of human platelet P2X1 and P2Y1 receptors to disruption of lipid rafts. Biochem Biophys Res Commun 343, 415-9.
  29. Carter, R.N. Tolhurst, G., Walmsley, G., Vizuete-Forster, M., Miller, N. & Mahaut-Smith, M.P. (2006). Molecular and electrophysiological characterisation of transient receptor potential ion channels in the primary murine megakaryocyte. Journal of Physiology, 576: 151-62.
  30. Martinez-Pinna, M.P., Gurung, I.S., Vial, C., Leon, C., Gachet, C., Evans, R.J. & Mahaut-Smith, M.P. (2005). Direct voltage control of signaling via P2Y1 and other Gaq-coupled receptors. J.Biol.Chem. 280, 1490-1498.
  31. Pitt, S.J., Martinez-Pinna, J., Barnard, E.A. & Mahaut-Smith, M.P. (2005). Potentiation of P2Y receptors by physiological elevations of extracellular K+ via a mechanism independent of Ca2+ influx. Molecular Pharmacology, 67, 1705-13
  32. Fung, C.Y.E, Brearley, C.A., Farndale, R.W. & Mahaut-Smith, M.P. (2005). A major role for P2X1 receptors in the early collagen-evoked Ca2+ responses of human platelets. Thrombosis & Haemostasis, 94, 37-40.
  33. Tolhurst, G., Vial, C., Leon, C., Gachet, C., Evans, R.J. & Mahaut-Smith, M.P. (2005). Interplay between P2Y1, P2Y12 and P2X1 receptors in the activation of megakaryocyte cation influx currents by ADP; evidence that the primary megakaryocyte represents a fully functional model of platelet P2 receptor signaling. Blood, 106, 1644-51.
  34. Horner, S., Menke, K., Hildebrandt, C., Kassack, M.U., Nickel, P., Ullmann, H., Mahaut-Smith, M.P. & Lambrecht, G. (2005). The novel suramin analogue NF864 selectively blocks P2X1 receptors in human platelets with potency in the low nanomolar range. Naunyn Schmiedbergs Archives Pharmacology, 372, 1-13.
  35. Mason, M.J., Simpson, A., Mahaut-Smith, M.P. & Robinson, H.P. (2005). The interpretation of current clamp recordings in the cell-attached patch clamp configuration. Biophysical Journal. 88, 739-50
  36. Martinez-Pinna, M.P., Tolhurst, G., Gurung, I.S., Vandenberg, J.I. & Mahaut-Smith, M.P. (2004). Sensitivity limits for voltage control of P2Y receptor-evoked Ca2+ mobilisation in the rat megakaryocyte. Journal of Physiology, 555, 61-70.
  37. Lu, Y., Mahaut-Smith, M.P., Huang, C.L.H. & Vandenberg, J.I. (2003). Mutant MiRP1 subunits modulate HERG K+ channel gating: A mechanism for pro-arrhythmia in Long QT Syndrome type 6. Journal of Physiology 551, 253-262.
  38. Vial, C., Pitt, S.J. Roberts, J., Rolf, M.G. Mahaut Smith, M.P. & Evans, R.J. (2003). Lack of evidence for functional ADP-activated human P2X1 receptors supports a role for ATP during hemostasis. Blood 102, 3646-3651.
  39. Mahaut-Smith, M.P., Thomas, D., Higham, A.B., Usher-Smith, J.A., Hussain, J.F, Martinez-Pinna, J., Skepper, J.N. & Mason, M.J. (2003). Properties of the megakaryocyte demarcation membrane system in living rat megakaryocytes. Biophysical Journal, 84, 2646-2654.

Books

  1. Platelets and Megakaryocytes, Vol 1. Functional Assays. Editors: J.M. Gibbins & M.P. Mahaut-Smith.: Methods in Molecular Biology, Vol 272, Humana Press Inc. Totawa, NJ. 2004. pp. 373
  2. Platelets and Megakaryocytes, Vol 2. Perspectives and Techniques. Editors: J.M. Gibbins & M.P. Mahaut-Smith.: Methods in Molecular Biology, Vol 273, Humana Press Inc. Totawa, NJ. 2004. pp 475.
  3. Platelets and Megakaryocytes, Vol 3. Additional Protocols and Perspectives. Editors: J.M. Gibbins & M.P. Mahaut-Smith.: Methods in Molecular Biology, Vol 788, Springer Science+Business Media, 2012 pp 400
  4. Platelets and Megakaryocytes, Vol 4. Advanced Protocols. Editors: J.M. Gibbins & M.P. Mahaut-Smith.: Methods in Molecular Biology, Vol 1812, Springer Science+Business Media, 2018, pp 287.

REVIEW ARTICLES, INVITED COMMENTARIES & CHAPTERS

  1. Osman, S., Dalmay, D. & Mahaut-Smith, M.P. (2018) Fluorescence approaches to image and quantify the demarcation membrane system in living megakaryocytes. Methods Mol. Biol. 1812, 195-215.
  2. Mahaut-Smith, M.P., Taylor, K.A, & Evans, R.J. (2016). Calcium signalling through ligand-gated ion channels such as P2X1 receptors in the platelet and other non-excitable cells. In press in “Calcium entry pathways in non-excitable cells”, Advances in Experimental Medicine and Biology, Springer; Edited by Juan A Rosado
  3. Taylor, K.A, Wright, J.R. & Mahaut-Smith M.P. (2015). Regulation of Pannexin-1 channels. Biochem Soc Trans. 43:502-7
  4. Mahaut-Smith, M.P. (2013). A role for platelet TRPC channels in the Ca2+ response that indices procoagulant activity. Science Signaling Jun 25;6:pe23
  5. Mahaut-Smith, M.P. (2012). The unique contribution of ion channels to platelet and megakaryocyte function. Journal of Thrombosis and Haemostasis, 10: 1722-1732.
  6. Tolhurst, G., Carter, R.N., Miller, N. & Mahaut-Smith, M.P. (2012). Purification of native bone marrow megakaryocytes for studies of gene expression. Methods Mol. Biol. 788, 259-273
  7. Mahaut-Smith, M.P., Jones, S. & Evans, R.J. (2011). The P2X1 receptor and platelet function. Purinergic Signalling, 7, 341-356.
  8. Fung, C.Y.E, Marcus, A.J., Broekman, M.J. & Mahaut-Smith, M.P. (2009). P2X1 receptor inhibition and soluble CD39 administration as novel mechanisms to widen the cardiovascular therapeutic window. Trends in Cardiovascular Medicine, 19, 1-5.
  9. Mahaut-Smith, M.P., Martinez-Pinna, J. & Gurung, I.S. (2008). A role for membrane potential in regulating GPCRs? Trends in Pharmacological Sciences 29: 421-9
  10. Mahaut-Smith, M.P., Tolhurst, G. & Evans, R.J. (2004). Emerging roles for P2X1 receptors in platelet function. Platelets, 15, 131-144.
  11. Mahaut-Smith, M.P. (2004). Patch clamp recordings of electrophysiological events in the platelet and megakaryocyte. In Platelets and Megakaryocytes, Vol 1. Editors: J.M. Gibbins & M.P. Mahaut-Smith.: Methods in Molecular Biology, Vol 272, Humana Press Inc. Totawa, NJ. 2004. pp 277-299.
  12. Mason, M.J. & Mahaut-Smith, M.P. (2004). Measurement and manipulation of intracellular Ca2+ in single platelets and megakaryocytes, In Platelets and Megakaryocytes, Vol 2. Editors: J.M. Gibbins & M.P. Mahaut-Smith.: Methods in Molecular Biology, Vol 273, Humana Press Inc. Totawa, NJ. 2004. pp 251-275.

Research

Mechanisms of platelet activation in thrombosis and haemostasis

My lab is particularly interested in the role of ion channels and calcium-dependent proteins in platelet function. For many experiments we use the megakaryocyte as a surrogate for studies of signalling in the tiny, anuclear platelet. Techniques: patch clamp, Ca2+-sensitive fluorescent indicators, quantitative RT- PCR, interference RNA, transgenic murine models, various assays of platelet function eg. aggregometry, adhesion, secretion, shape change.

Development of platelet-producing megakaryocytes from stem cells

We are investigating the mechanisms by which platelets develop within their precursor cell, the megakaryocyte, with a focus on its complex plasma membrane invagination system. Known as the demarcation membrane system (DMS), it shares several properties with the transverse tubular system of cardiac myocytes and can be studied using patch clamp or styryl fluorescent indicators. We are currently exploring the mechanism whereby the DMS and cardiac T tubules become detached form the surface membrane by cationic amphiphilic drugs (Osman et al. 2016). Techniques: single and multi-photon confocal microscopy, patch clamp, interference RNA, single cell RT-PCR.

Interactions between ion channels and GPCRs

We are investigating how ion channels can modulate signalling through GPCRs. In particular, we have identified a marked ability for certain Gq-coupled receptors (eg P2Y1) to be directly modulated by the cell membrane potential. Techniques: Patch clamp, Ca2+-sensitive fluorescent indicators, GFP fusion proteins, FRET

Image 1
A. Experiments by Sarah Jones and Eleanor Fung; See Fung et al. 2012 Blood 119:3613-21

Image 2
B. Impermeant membrane indicators (eg. di 8-ANEPPS) gain access to the demarcation membrane system throughout the extranuclear volume of the megakaryocyte (Mahaut-Smith et al. 2003; Biophys J. 84 2646)

Image 3
C. Transmission electron microscopy images of the megakaryocyte cytoplasm before (left) and after (right) treatment with a cationic amphiphilic drug, which collapses the complex demarcation membrane system. (Experiment by Sangar Osman and Natalie Allcock)

Main Collaborators

  • Prof. Richard Evans, Leicester
  • Dr Catherine Vial, Leicester
  • Dr Richard Rainbow, Leicester
  • Dr John Mitcheson, Leicester
  • Prof. Jon Gibbins, Reading
  • Dr Steve Thomas, Birmingham
  • Prof. Steve Watson, Birmingham
  • Dr Juan Martinez-Pinna, Alicante

Supervision

Possible future PhD projects are available in the general area of ion channels, Ca2+ signalling and membrane invagination systems, with a particular focus on their roles in megakaryocytes, platelets and ventricular myocytes.

Recent PhD research projects

  • Activation of platelet Ca2+ channels by shear stress and FcΥRIIa receptors
  • Ca2+ signalling during platelet: tumour cell interactions
  • Membrane invagination systems of the platelet, megakaryocyte and ventricular myocyte
  • Synergy between P2 receptor-evoked signalling pathways -Pannexin-1 function in the platelet
  • Signalling via P2X1 receptors

Media

Together with Prof. Jonathan Gibbins (University of Reading), I have edited four volumes of the popular Methods in Molecular Biology books published by Humana Press (now Springer). These four volumes contain more than 100 Chapters in which experts across the globe have shared their knowledge and expertise of a wide variety of standard and advanced techniques for the study of platelets and megakaryocytes.

 

 

Vol 4 Gibbins Mahaut-Smith

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Department of Molecular and Cell Biology

T: +44(0)116 229 7038
E: MolCellBiol@le.ac.uk

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