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Department of Physiology, Development and Neuroscience

 

Research

Alterations in ion channel expression is an established finding in many cancers. Expression of distinct channel types in malignacies may underlie altered patterns of gene expression, tumour invasion and malignant cell proliferation. Examination of the alterations in channel phenotype can be used as a diagnostic tool for identification of some cancer subtypes. Driven by my long standing interest in megakaryocyte calcium signaling and ion channel expression, my laboratory has focused upon the documented loss of voltage-activated potassium channel function in megakaryocytes from patients suffering from acute myelogenous leukaemia. Suppression of this critical membrane potential controlling ion channel is associated with the malignacy since chemotherapy-induced remission results in normal voltage-activated potassium channel function.

These findings raised a simple, yet crucial question. In the face of loss of this ion channel, what is setting the resting membrane potential? Using both whole cell and single channel patch clamp recordings in cell lines of leukaemic origin, we have demonstrated the expression of a previously unappreciated potassium conductance that is inhibited by intracellular free magnesium. We refer to this conductance as the Magnesium Inhibited Potassium (MIP) conductance. A key role of this MIP conductance is to set a hyperpolarised resting membrane potential in the face of constitutive expression of the non-selective cation current, TRPM7.  Our experiments demonstrate that without the MIP conductance, TRPM7 would depolarise the cell to values close to 0 mV, highlighting the importance of MIP current expression in hyperpolarising the resting membrane potential.

Additional work in the lab has demonstrated an absolute requirement for the MIP current for optimal Calcium Release Activated (CRAC) calcium entry following depletion of intracellular calcium stores. The requirement for the MIP conductance in this response arises from the absolute requirement for a negative membrane potential to support sufficient CRAC-mediated calcium entry to activate the calcium-activated potassium channel, KCa3.1. Activation of KCa3.1 leads to marked hyperpolarisation and augmented CRAC-mediated calcium entry via a simple feed-forward mechanism.  It is our ultimate aim to use modulation of ion channel conductances for the purpose of disrupting malignant cell function in acute myelogenous leukaemia.

Collaborators

Professor Andres Floto, Addenbrroke’s Hospital, Department of Medicine and the Cambridge Institute for Medical Research
Dr Steve Lee, Department fo Chemistry, University of Cambridge
Professor William Colledge, Department of Physiology, Development and Neuroscience, University of Cambridge
Dr Stewart Sage, Department of Physiology, Development and Neuroscience, University of Cambridge

Publications

Key publications: 

Littlechild R, Zaidman N, Khodaverdi D, Mason MJ, (2015), Block of KCa3.1 and Membrane Hyperpolarisation by 2-Aminoethoxydiphenyl Borate (2-APB) in Human Erythroleukemia (HEL) Cells: Implications for the Interpretation of 2-APB Inhibition of Ca2+ Release Activated Ca2+ (CRAC) Entry, Cell Calcium, 57, 76-88

Stoneking CJ, Mason MJ, (2014), Mg2+ modulation of the single channel properties of Kca3.1 in human erythroleukemia cells, Pflügers Arch. 466, 1529-1539

Stoneking CJ, Shivakumar O, Nicholson Thomas D, Colledge WH, Mason MJ, (2013), Voltage dependence of the Ca2+-activated K+ channel KCa3.1 in human erythroleukemia cells, Am. J. Physiol. 304, C858-C872

Mason MJ, Schaffner C, Floto RA, Teo QA, (2012), Constitutive expression of a Mg2+ inhibited K+ current and a TRPM7-like current in human erythroleukemia cells, Am. J. Physiol. 302, C853-C867

Harper MT, Mason MJ, Sage SO, Harper AGS, (2010), Phorbol ester-evoked Ca2+ signaling in human platelets is via autocrine activation of P2X1 receptors, not a novel non-capacitative Ca2+ entry, J. Thrombs Haemostasis, 8, 1604-1613

Harper AGS, Mason MJ, Sage SO, (2009), A key role for dense granule secretion in potentiation of the Ca2+ signal arising from store-operated calcium entry in human platelets, Cell Calcium, 45, 413-420

Mahaut-Smith MP, Thomas D, Higham AB, Usher-Smith JA, Hussain JF, Skepper JN, Mason MJ, (2003), Properties of the megakaryocyte demarcation membrane system in living megakaryocytes revealed by confocal fluorescence and whole-cell patch clamp techniquesBiophysical J. 84, 2646-2654

Mahaut-Smith MP, Hussain JF, Mason MJ, (1999), Depolarisation-evoked Ca2+ release in a non-excitable cell, the rat megakaryocyte, J. Physiol. 515, 385-390

Mason MJ, Mahaut-Smith MP, Grinstein S, (1991), The role of intracellular Ca2+ in the regulation of the plasma membrane Ca2+ permeability of unstimulated rat lymphocytes, J. Biol. Chem. 266, 10872-10879

Mason MJ, Garcia-Rodriguez C, Grinstein S, (1991), Coupling between intracellular Ca2+ stores and the Ca2+ permeability of the plasma membrane: Comparison of the effects of thapsigargin, 2,5-di-(tert-butyl)1,4-hydroquinone and cyclopiazonic acid in rat thymic lymphocytes, J. Biol. Chem. 266, 20856-20862

Teaching and Supervisions

Teaching: 

Course organiser: Integrative Physiology Theme Organiser, NST Part II Physiology, Development and Neuroscience

Lecturer in: Homeostasis MVST 1A, Physiology of Organisms NST 1A, Physiology NST 1B, PDN Part II Cell Module

University Lecturer

Contact Details

+44 (0) 1223 333849, Fax: +44 (0) 1223 333840
Email address: