Professor Andrew Tinker

Profile

I trained as a physician at Oxford and then London before undertaking pre and postdoctoral training in the UK and USA working on cardiac excitation-contraction coupling and the molecular properties of potassium channels. I returned to the UK and worked for a long time at University College, London as a Wellcome Trust Senior Research fellow in Clinical Science and subsequently Professor of Molecular Medicine. In 2011 I moved to Barts and the London School of Medicine and Dentistry to take up a Chair of Cardiac Electrophysiology. In recognition of this work I was elected a Fellow of the Academy of Medical Sciences in 2006. I have worked on funding committees for the British Heart Foundation, MRC, UKRI and Wellcome Trust. I was previously Head of Clinical Pharmacology at the William Harvey Research Institute.

Research

Group members

Fahad Al Hattali, Greg Funge, Aled Jones, Keat-Eng Ng, Muriel Nobles, Kaya Olczak, Nikayla Patel, Sonia Sebastian, Yaqob Taleb, Alison Thomas, Elena Tsisanova, Darren Wilson

Summary

My scientific interests revolve around the molecular properties and regulation of cardiac and smooth muscle cell excitability with a particular focus on cardiac arrhythmia, potassium channels and G-protein signalling.  Specifically we have studied:

• ATP-sensitive potassium channels (K_ATP). In our most recent studies, and we have sought to understand the physiological function of unique populations of channels. To do this we have developed and validated unique murine genetic models where it is possible to conditionally delete the pore forming subunits in a particular tissue and\or at a certain time. We have shown that K_ATP in smooth muscle are important in controlling blood pressure, govern blood flow to key organs such as the brain and limit cardiac ischaemic damage. Endothelial K_ATP channels are constituted of Kir6.1, control calcium entry and potentially mediator release and limit cardiac ischaemic damage. KATP channels are also present in the sinoatrial node and can control heart rate and govern the response to hypoxia. We have previously studied the regulation of these channel complexes by protein kinases and anionic phospholipids and their propensity to form unique complexes through heteromultimerisation.
• G-protein gated inward rectifier potassium channels. There is substantial data showing that Kir3.0 channels are regulated by G-protein betagamma subunits and in many ways they are the canonical effector for such signalling. However our studies showed a central role for the alpha subunit and other proteins in shaping the cellular response and how this translates into the physiological control of heart rate.
• Cardiac Arrhythmia. I have broad interests in cardiac arrhythmia with a number of clinical collaborations on channelopathies such as the long QT syndrome, the role of cell signalling in arrhythmogenesis and cardiomyopathies. For example, we have shown that a large number of mutations in potassium channels fail to traffic properly to the plasma membrane in the long QT syndrome, the potential role of regulators of G-protein signalling in AF and that there are early changes in electrical phenotype in arrhythmogenic cardiomyopathy.

In ongoing work we are also examining candidate proteins that have emerged from GWAS studies in cardiovascular traits, the role of autonomic innervation in controlling cardiac excitability and examining the genetic determinants of novel ECG traits. We (Professors Tinker, Munroe and Lambiase) have established the QMUL-UCL Electrogenomics Group which meets on a monthly basis sharing progress across a variety of projects on the genetic underpinning of ECG traits and arrhythmia. The group now numbers over 10 academics from QMUL and UCL and includes geneticists, engineers, cardiologists and physiologists.

Key Publications

Full list of publications

• Ng, K.E., Delaney, P.J., Thenet, D., Murtough, S., Webb, C.M., Zaman, N., Tsisanova, E., Mastroianni, G., Walker, S.L.M., Westaby, J.D., Pennington, D.J., Pink, R., Kelsell, D.P.* & Tinker, A.* (2021) Early inflammation precedes cardiac fibrosis and heart failure in desmoglein 2 murine model of Arrhythmogenic Cardiomyopathy. Journal of Cell and Tissue Research 386, 79-98.
• Sebastian, S., Nobles, M., Tsisanova, E., Ludwig, A., Munroe, P.B. & Tinker, A. (2021) The role of resistance to inhibitors of cholinesterase 8b in the control of heart rate. Physiological Genomics 53, 150-9.
• Li, Y., Aziz, Q., Anderson, N., Ojake, L. & Tinker, A. (2020) Endothelial ATP-Sensitive Potassium Channel Protects Against the Development of Hypertension and Atherosclerosis. Hypertension 76, 776-84.
• Aziz, Q., Chen, J., Moyes, A.J., Li, Y., Anderson, N.A., Ang, R., Aksentijevic, D., Sebastian, S., Hobbs, A.J., Thiemermann, C. & Tinker, A. (2020) Vascular K_ATP channels protect from cardiac dysfunction and preserve cardiac metabolism during endotoxemia. Journal of Molecular Medicine 98, 1149-60.
• Ramírez, J., van Duijvenboden, S., Young, W.J., Orini, M., Lambiase, P.D., Munroe, P.B. & Tinker, A. (2020) Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval. American Journal of Human Genetics 106, 764-78.
• HOSFORD, P.S., CHRISTIE, I.N., NIRANJANC, N., AZIZ, Q., ANDERSON, N.,  ANG, R., MARK F. LYTHGOE, M.F., WELLS, J.A., TINKER, A.* AND GOURINE, A.V*. (2019) A critical role for the ATP-sensitive potassium channel subunit KIR6.1 in the control of cerebral blood flow. Journal of Cerebral Blood Flow and Metabolism 39, 2089-2095
• AZIZ, Q., FINLAY, M., MONTAIGNE, D., OJAKE, L., LI, Y., ANDERSON, N., LUDWIG, A. & TINKER A. (2018) ATP-sensitive potassium channels in the sinoatrial node contribute to heart rate control and adaptation to hypoxia. Journal of Biological Chemistry 293, 8912-8921.
• ANG, R., Mastitskaya, S., Hosford, p., basalay, M., specterman, m., aziz, q., li, y., orini, m., taggart, p., lambiase, p.d., gourine, a., tinker, a.* & Gourine, a.v.* (2018) Modulation of Cardiac Ventricular Excitability by GLP-1 (Glucagon-Like Peptide-1). Circulation: Arrhythmia and Electrophysiology 11, e006740
• AZIZ, Q., LI, Y., ANDERSON, N., OJAKE, L., TSISANOVA, E. & TINKER, A. (2017) Molecular and functional characterization of the endothelial ATP-sensitive potassium channel. Journal of Biological Chemistry 292, 17587-97.
• OPEL, A., NOBLES, M., MONTAIGNE, D., FINLAY, M., ANDERSON, N., BRECKENRIDGE, R. & TINKER, A. (2015) Absence of the Regulator of G-protein signaling, RGS4, predisposes to Atrial Fibrillation and is associated with Abnormal Calcium Handling. Journal of Biological Chemistry 290, 19233-44.
• AZIZ, Q., THOMAS, A.M., GOMES, J., ANG, R., SONES, W.R., LI, Y., NG, K.E., GEE, L. & TINKER, A. (2014) The ATP-Sensitive Potassium Channel Subunit, Kir6.1, in Vascular Smooth Muscle Plays a Major Role in Blood Pressure Control. Hypertension 64, 523-9.  
• SEBASTIAN, S., ANG, R., ABRAMOWITZ, J., WEINSTEIN, L.S., CHEN, M., LUDWIG, A., BIRNBAUMER, L.  & TINKER, A. (2013) The in-vivo regulation of heart rate in the murine sinoatrial node by stimulatory and inhibitory heterotrimeric G-proteins. American Journal of Physiology 305, R435-42.
• GOMES, J., FINLAY, M., AHMED, A.K., CIACCIO, E.J., ASIMAKI, A., SAFFITZ, J.E., NOBLES, M., SYRRIS, P., CHAUBEY, S., McKENNA, W.J., TINKER, A.* & LAMBIASE, P.D.* (2012) Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin - A combined murine and human study. European Heart Journal 33, 1942-53.
• THOMAS, A.M., HARMER, S.C., KHAMBRA, T. & TINKER, A. (2011) Characterisation of a binding site for anionic phospholipids on KCNQ1. Journal of Biological Chemistry. 286, 2088-100.
• SCHWARZER, S., NOBLES, M. & TINKER, A. (2010) Do caveolae have a role in the fidelity and dynamics of receptor activation of G-protein gated inwardly rectifying potassium channels? Journal of Biological Chemistry 285, 27817-26. PMCID: 2934649
• ZUBERI, Z., NOBLES, M., SEBASTIAN, S., DYSON, A., SHIANG, Y., BRECKENRIDGE, R., BIRNBAUMER, L. & TINKER, A. (2010) Absence of the inhibitory G-protein, Gai2, predisposes to ventricular cardiac arrhythmia. Circulation: Arrhythmia and Electrophysiology 3, 391-400.
• ZUBERI, Z., BIRNBAUMER, L. & TINKER, A. (2008) The role of inhibitory heterotrimeric G-proteins in the control of in-vivo heart rate dynamics. American Journal of Physiology (Regul Integr Comp Physiol) 295, R1822-30.
• CAMPANELLA, M., CASSWELL, E., CHONG, S., FARAH, Z., WIECKOWSKI, M.R., ABRAMOV, A.R., TINKER, A. & DUCHEN, M.R. (2008) Regulation of mitochondrial structure and function by IF1, the endogenous inhibitor of the mitochondrial ATPase. Cell Metabolism 8, 13-25.
• NOBLES, M., BENIANS, A. & TINKER, A. (2005). Heterotrimeric G proteins precouple with G-protein coupled receptors in living cells. Proceedings of the National Academy of Sciences (USA) 102, 18706-11. PMCID: 1317907WILSON, A.J., QUINN, K.V., GRAVES, F.M., BITNER-GLINDZICZ, M. & TINKER, A. (2005) Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1). Cardiovascular Research 67, 476-86. PMID: 15935335
• BENIANS, NOBLES, M., HOSNY, S. & TINKER, A. (2005). Regulators of G-protein signalling form a quaternary complex with the agonist, receptor and G-protein: a novel explanation for the acceleration of signalling activation kinetics. Journal of Biological Chemistry 280, 13383-13394.
• QUINN, K., GIBLIN, J., & TINKER, A. (2004) A multi-site phosphorylation mechanism for protein kinase A activation of the smooth muscle ATP-sensitive K⁺ channel. Circulation Research 94, 1359-1366.
• QUINN, K., CUI, Y., GIBLIN, J., CLAPP, L.H. & TINKER, A. (2003) Do anionic phospholipids serve as cofactors or second messengers for the regulation of activity of cloned ATP-sensitive K+ channels? Circulation Research 93, 646-655. PMID: 12970116
• BENIANS A., LEANEY, J.L., & TINKER, A (2003). Agonist unbinding from receptor dictates the nature of deactivation kinetics of G-protein gated K+ channels. Proceedings of the National Academy of Sciences (USA) 100, 6239-44.
• LEANEY, J.L. & TINKER, A. (2000) The role of members of the pertussis toxin-sensitive family of G proteins in coupling receptors to the activation of the G protein-gated inwardly rectifying potassium channel. Proceedings of the National Academy of Sciences (USA) 97, 5651-5656.
• LEANEY, J.L., MILLIGAN, G. & TINKER, A. (2000) The G-protein alpha subunit has a key role in determining the specificity of coupling to, but not the activation of, G protein-gated inwardly rectifying K⁺ channels. Journal of Biological Chemistry 275, 921-929.
• TINKER, A, JAN Y.N. & JAN L.Y. (1996) Regions responsible for the assembly of inwardly rectifying potassium channels. Cell 87, 857-868.
  
  

Collaborators