Martin Bootman
Career History
1985 - 1989 University of East Anglia, Biological Sciences B.Sc. (Hons) First class(Awarded the Rank Hovis MacDougall Scholarship). 15-month industrial placement working in the Exploratory Biochemistry Section at Ciba-Geigy Pharmaceuticals in Horsham, Sussex.
1989 - 1992 Department of Zoology, University of Cambridge. Ph.D. with Prof. Sir M.J. Berridge FRS
1992 - 1996 Research Fellowship at Christ's College, Cambridge.
1994 Four-month visit to work with Prof. Ludwig Missiaen in the Laboratory of Prof. Rik Casteels K.U.Leuven, Belgium. Recipient of a fellowship from the 'Onderzoeksfonds' of the K.U.Leuven.
1995 - 2004 Royal Society University Research Fellowship. Position renewed for 3 years in 2000 and for a further year in 2003.
2004- Project Leader, Laboratory of Molecular Signalling, Babraham Institute, Babraham, Cambridge.
Functional characterisation of the calcium signalling toolkit
Calcium regulates a diverse array of cellular processes. For example, elevation of intracellular calcium is one of the first events to occur following sperm/egg fusion at fertilisation. Pulsatile calcium increases trigger contraction of the beating heart. Dysregulation of calcium homeostasis is known to underlie a variety of pathological conditions and can trigger cell death.
The Calcium Group within the Laboratory of Molecular Signalling has a long-standing interest in how cells generate and interpret calcium signals. Cellular calcium signals are highly versatile- they can occur as brief events localised to specific regions within cells or traverse whole tissues in a repetitive manner. The enormous diversity of calcium signals arises from the complex interplay of different mechanisms that serve to increase or decrease calcium within cells. The types of responses that a cell can display are a function of its ‘calcium signalling proteome'. Such proteomes are cell specific: no two cell types utilise exactly the same combinations of calcium signalling systems and they therefore have unique responses.
The goal of our research is to characterise the elements that make up calcium signalling proteomes, to understand the factors controlling the expression of different elements of such proteomes, and also to elucidate how cells detect and respond to their specific calcium patterns. Our work therefore has the intertwined themes of characterising calcium signalling machinery and understanding physiological/pathological responses to calcium.
Over the past year, we have particularly focused on mechanisms regulating calcium release from intracellular stores. Mobilisation of calcium stores is achieved through the activation of channels expressed on the surface of endomembrane compartments, such as the endoplasmic reticulum or sarcoplasmic reticulum. A principal type of calcium release channel is the inositol 1,4,5-trisphosphate receptor (InsP3Rs). These are large (~1200 kDa) tetrameric proteins, with an amino-terminal domain projecting into the cytoplasm, and an integral Ca2+ channel formed by six membrane-spanning regions in the carboxy-terminal portion of each subunit. InsP3 binding within residues 226-576 of the amino terminus causes a conformational change that promotes channel opening.
Between the InsP3 binding site and the transmembrane regions is a large stretch of amino acids where a significant proportion of regulatory interactions occur. InsP3Rs are expressed and participate in Ca2+ release within almost all mammalian tissue, although their function in some cell types is unclear. Three InsP3R isoforms have been cloned and splice variants have been described, leading to the possibility of heteromultimeric channels with distinctive properties based on their subunit content.
We are currently using mass spectrometry and bioinformatics approaches to examine proteins that interact with InsP3Rs. So far, a group of >15 proteins with significant roles in cell biology have emerged as binding partners and regulators of InsP3Rs. One example is the anti-apoptotic protein Bcl-2, which is a key regulator of cell death. Our work has demonstrated that this protein binds to InsP3Rs, decreases the amount of calcium released during cell stimulation and thereby reduces apoptosis. The precise mechanism by which Bcl-2 exerts this effect and its binding site are currently under investigation.
Other InsP3R binding partners include cytochrome C, calmodulin and members of the neuronal calcium sensor family. In addition to these proteins with known cellular functions, we are finding InsP3R binding partners with, as yet, unknown function. Furthermore, InsP3Rs also dock kinases, phosphatases and cytoskeletal components, suggesting that they posses the machinery to receive and convey messages inside a cell. In addition to revealing the complexity of InsP3R regulation, these studies will provide a basis for an integrative view of the role of InsP3Rs and calcium release in cell behaviour.
We are also interested in the modulation of cardiac myocytes by InsP3Rs. In particular, we have focussed on the regulation of excitation contraction-coupling in cardiomyocytes from the atrial chambers of the heart. We have demonstrated that perfusion of atrial cardiac myocytes with cardioactive hormones, such as endothelin-1 (ET-1), leads to an increase in the amplitude of calcium transients during excitation contraction-coupling. This is a beneficial ‘positive inotropic' effect that causes greater contractility and can increase blood flow.
However, concomitant with the stimulation of contractility, ET-1 triggers spontaneous calcium transients during otherwise quiet diastolic periods. Such spontaneous calcium transients can lead to unsynchronised activity in the heart, known as arrhythmia.
Although it is established that ET-1 activates the pathway that leads to InsP3 production, a potential role for InsP3-induced calcium signalling in the heart has been generally discounted. We have shown that cardiac myocytes express functional InsP3Rs that can augment the contractility of cardiac cells, but may be even more significant for the generation of arrhythmias.
Roderick HL, Bootman MD (2007) Pacemaking, arrhythmias, inotropy and hypertrophy; the many possible facets of InsP3 signalling in cardiac myocytes.
Journal of Physiology 581 883-884
http://dx.doi.org/10.1113/jphysiol.2007.133819
Bootman MD, Higazi DR, Coombes S, Roderick HL (2006) Calcium signalling during excitation-contraction coupling in mammalian atrial myocytes.
Journal of Cell Science 119 3915-3925
http://dx.doi.org/10.1242/jcs.03223
Lui Q, Walker SA, Gao D, Taylor JA, Dai Y-F, Arkell RS, Bootman MD, Roderick HL, Cullen PJ, Lockyer PJ (2005) CAPRI and RASAL impose different modes of information processing on Ras due to contrasting temporal filtering of Ca2+.
Journal of Cell Biology 170 183-190
http://dx.doi.org/10.1083/jcb.200504167
Shim S, Goh EL, Ge S, Sailor K, Yuan JP, Roderick HL, Bootman MD, Worley PF, Song H, Ming G-L (2005) XTRPC1-dependent chemotropic guidance of neuronal growth cones.
Nature Neuroscience 8 730-735
http://dx.doi.org/10.1038/nn1459
Chen R, Valencia I, Zhong F, McColl KS, Roderick HL, Bootman MD, Berridge MJ, Conway SJ, Holmes AB, Mignery GA, Velez P, Distelhorst CW (2004) Bcl-2 functionally interacts with inositol 1,4,5-trisphospate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate.
Journal of Cell Biology 166 193-203
http://dx.doi.org/10.1083/jcb.200309146
Kasri NN, Holmes AM, Bultynck G, Parys JB, Bootman MD, Rietdorf K, Missiaen L, McDonald F, De Smedt H, Conway SJ, Holmes AB, Berridge MJ, Roderick HL (2004) Regulation of InsP3 receptor activity by neuronal Ca2+-binding proteins.
EMBO Journal 23 312-321
http://dx.doi.org/10.1038/sj.emboj.7600037
Mackenzie L, Roderick HL, Berridge MJ, Conway SJ, Bootman MD (2004) The spatial pattern of atrial cardiomyocyte calcium signalling modulates contraction.
Journal of Cell Science 117 6327-6337
http://dx.doi.org/10.1242/jcs.01559
Ciccolini F, Collins TJ, Sudhoelter J, Lipp P, Berridge MJ, Bootman MD (2003) Local and global spontaneous calcium events regulate neurite outgrowth and onset of GABAergic phenotype during neural precursor differentiation.
Journal of Neuroscience 23 103-111
http://www.jneurosci.org/cgi/content/full/23/1/103
Collins TJ, Berridge MJ, Lipp P, Bootman MD (2002) Mitochondria are morphologically and functionally heterogeneous within cells.
EMBO Journal 21 1616-1627
http://dx.doi.org/10.1093/emboj/21.7.1616
Mackenzie L, Bootman MD, Laine MK, Berridge MJ, Thuring JW, Holmes AB, Li W-H, Lipp P (2002) The role of inositol 1,4,5-trisphosphate receptors in Ca2+ signalling and the generation of arrhythmias in rat atrial myocytes.
Journal of Physiology 541 395-409
http://dx.doi.org/10.1113/jphysiol.2001.013411
