Professor Martyn Mahaut-Smith

Tel:  0116 229 7135      Email:  mpms1@le.ac.uk

Research Interests and Techniques

Mechanisms of platelet activation in thrombosis and haemostasis

We are particularly interested in the role of ion channels and calcium-dependent proteins. 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. 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

Martin Mahaut-Smith Image 1

Figure 1. The major contribution of P2X1 receptors to early collagen-evoked Ca2+ signalling in the platelet. ATP-gated P2X1 receptors are the only Ca2+-permeable ligand-gated ion channel reported to date on the platelet plasma membrane; it therefore represents one of the fastest means whereby vascular injury can activate a Ca2+ increase during haemostasis and thrombosis. For further details see Fung et al. 2007. J.Thromb.Haemost 5: 910-7.

Martin Mahaut-Smith Image 2

Figure 2. Confocal fluorescence imaging of the demarcation membrane system of the megakaryocyte. The confocal images show the staining pattern of membranes continuous with the extracellular space (dye: 10 mM di-8-ANEPPS). The complex demarcation membrane system, which provides a reservoir of membranes for future platelet production, can be seen throughout the extranuclear space of the large megakaryocyte. Small marrow cells lack this membrane system and stain as halos. For further details see Mahaut-Smith et al. 2003, Biophys. J. 84: 2646-54

Research Group and Funding

sources of funding

British Heart Foundation

BBSRC

MRC

Leicester Cardiovascular Biomedical Research Unit

Iraqi Government

Group members

Alex Bye

Sangar Osman

Kirk Taylor

Dr Joy Wright

Zeki Ilkan

Dr Lorenza Francescut

Tayyaba Iftikhar

Main collaborators

Professor Richard Evans, University of Leicester
Professor Alison Goodall, University of Leicester

Professor Jon Gibbins, University of Reading
Professor Richard Farndale, University of Cambridge
Dr Koji Eto, University of Tokyo

Dr Stefan Amisten, KCL
Dr Juan Martinez-Pinna, University of Alicante

Recent Publications

ORIGINAL RESEARCH PAPERS

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.

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

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.

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. doi: 10.1038/ncomms3564

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.

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, http://dx.plos.org/10.1371/journal.pone.0029946).

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

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

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.

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.

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

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.

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.

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

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

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

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.

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.

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

REVIEWS

Taylor, K.A, Wright, J.R. & Mahaut-Smith M.P. (2015). Regulation of Pannexin-1 channels. Biochem Soc Trans. 43:502-7

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

Mahaut-Smith, M.P. (2012). The unique contribution of ion channels to platelet and megakaryocyte function. Journal of Thrombosis and Haemostasis, 10: 1722-1732.

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

Mahaut-Smith, M.P., Jones, S. & Evans, R.J. (2011). The P2X1 receptor and platelet function. Purinergic Signalling, 7, 341-356.

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.

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

BOOKS

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

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.

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.

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Department of Molecular and Cell Biology
Henry Wellcome Building
Lancaster Road
Leicester
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T:  +44(0)116 229 7038
F:  +44(0)116 229 7123
MolCellBiol@le.ac.uk

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Redfearn Lecture 2017

To Be Confirmed