Prof Mark Evans
One of my primary areas of research is the role of -activated protein kinase in mediating chemotrasduction by hypoxia in oxygen-sensing cells.
- 2009 - present: Chair of Cellular Pharmacology, University of Edinburgh
- 2008 - present: Senior Academic Fellow, University of Edinburgh
- 2007 - 2008: Professor, Personal Chair in Cell Biology, University of East Anglia
- 2005 - 2007: Reader, University of St Andrews
- 2002 - 2005: University Lectureship, University of St Andrews
- 2001 - 2002: Wellcome Trust Non-Clinical Lectureship, University of St Andrews
- 1996 - 2001: Wellcome Trust Career Development Research Fellow, University Department of Pharmacology, University of Oxford
- 1994 - 1996: Visiting Research Fellow, Department of Pharmacology, United Medical and Dental Schools, St. Thomas's Hospital, University of London
- 1993 - 1994: Postdoctoral Research Fellow, Department of Pharmacology, St George's Hospital Medical School, University of London
- 1992 - 1993: Postdoctoral Research Fellow, Department of Pharmacology, United Medical and Dental Schools, St Thomas's Hospital, University of London
- 1990 - 1992: Postdoctoral Research Fellow, Department of Preclinical Veterinary Sciences, University of Edinburgh
Current and future Research plans
Our investigations focus on the regulation by hypoxia of cardio-respiratory function in health and disease, from the hypoxic ventilatory response to sleep apnoea, and from hypoxic pulmonary vasoconstriction to pulmonary hypertension. We employ an integrative approach to the identification and characterisation of targets that may offer novel therapeutic strategies, learning from outcomes of investigations on intracellular signalling pathways, cell and system function, and behavioural responses of the whole animal. Our research falls into 3 key areas:
Regulation of breathing and oxygen supply by the AMP-activated protein kinase
In 2006 I postulated that the AMP-activated protein kinase (AMPK), which is key to the cell autonomous regulation of metabolic homeostasis, might serve to regulate oxygen and thus energy (ATP) supply at the whole body as well as the cellular level. In this respect our focus was on the hypoxic ventilatory response and hypoxic pulmonary vasoconstriction, in short the regulation of breathing during hypoxia and ventilation-perfusion matching at the lung.
Key to our hypothesis was the proposal that AMPK might directly phosphorylate and regulate ion channel complexes and thus mediate the activities of those oxygen-sensing cells that underpin each of these processes.
It is generally accepted that the hypoxic ventilatory response is determined by a fall in arterial oxygen tension and consequent increases in afferent discharge from the carotid bodies to the brainstem, which restores oxygen supply. We recently demonstrated that the AMPK-α1 catalytic subunit is indeed critical to this process, and that AMPK deficiency precipitates hypoventilation and apnoea during hypoxia.
Contrary to current consensus, however, afferent input responses from the carotid body remained normal following AMPK deletion, and our findings suggest that AMPK regulates ventilation at the level of the caudal brainstem.
We are therefore testing the hypothesis that AMPK coordinates the activation by hypoxia of nuclei within brainstem respiratory networks through its capacity to integrate central hypoxic stress with applied metabolic stress, the latter being delivered by those afferent chemosensory inputs that provide an index of peripheral hypoxic status. AMPK activation may thereby support increases in respiratory drive, while deficiencies in its expression may precipitate apnoea during, for example, sleep and ascent to altitude.
Our unpublished studies indicate that AMPK is also necessary for hypoxic pulmonary vasoconstriction and thus ventilation-perfusion matching at the lungs. Paradoxically, further investigation has revealed that AMPK deficiency precipitates pulmonary hypertension, in part by altering ion channel trafficking and autophagic flux.
Given the above, our future aim is to determine how tissue-specific deficiencies in AMPK expression may arise, and to characterise the mechanisms by which AMPK deficiency may precipitate pulmonary hypertension and sleep disordered breathing.
Two Pore Channels and the regulation of endolysosomal function
In collaboration with Mike Zhu (University of Texas Medical School at Houston) we identified Two Pore Channels (TPCs) as a novel family of ion channels that are principally targeted to endolysosomes, and may be gated by cellular messengers such as, for example, the Ca2+ mobilising messenger NAADP.
We have shown that three subtypes of TPC are found in mammals, of which only TPC1 and TPC2 are expressed in humans, rats and mice. TPC2 is targeted to lysosomes and TPC1 to endosomes, and both support Ca2+ release from their designate acidic store. Our present and future aim is to determine how TPCs might contribute to protein trafficking and autophagy in pulmonary arterial myocytes, and the mechanism by which hypoxia and AMPK may modulate these activities.
The role of intracellular nanojunctions in delivering site- and function-specific Ca2+ signals
These investigations are founded on the original hypothesis (van Breemen, Fameli and Evans) that the sarco/endoplasmic reticulum (S/ER) performs its many functions by communicating with the plasma membrane, lysosomes, nucleus and other organelles across cytoplasmic nanospaces, which are defined by membrane-membrane nanojunctions that are less than 50 nm across.
We aim to determine whether or not nanojunctions of the SR and the cytoplasmic nanospaces they confer provide for the effective control of cellular functions as diverse as contraction, gene expression and cell proliferation, and how they are utilised to accomplish site- and function-specific signalling.
To date our data suggest that accurate Ca2+ signalling is determined by its restricted diffusion within cytoplasmic nanospaces conferred those membrane nanojunctions that demarcate them, and by the strategic positioning within a given nanojunction of designate Ca2+ pumps and release channels.
- Dr Oluseye Ogunbayo (Postdoctoral Fellow)
- Dr Javier Morel-Sanz (Postdoctoral Fellow)
- Jingxian Duan (PhD student)
- Sandy Hartmann (PhD student)
- D. Grahame Hardie, University of Dundee.
- Michael Zhu, University of Texas Medical School at Houston, USA.
- Jianjie Ma, Case Western, USA.
- Casey van Breemen, University of British Columbia.
- Eric Schirmer, Wellcome Trust Centre for Cell Biology, University of Edinburgh.
Javier Moral-Sanz,*Sophronia A. Lewis,* Sandy MacMillan, Fiona A. Ross, Adrian Thomson, Benoit Viollet, Marc Foretz, Carmel Moran, D. Grahame Hardie, and A. Mark Evans (Sci. Signal. 02 Oct 2018). The LKB1–AMPK-α1 signaling pathway triggers hypoxic pulmonary vasoconstriction downstream of mitochondria Vol. 11, Issue 550, eaau0296 Click here for: Summary - Abstract - Reprint - Full text.
MacMillan S, Evans AM(2018). AMPK-α1 or AMPK-α2 Deletion in Smooth Muscles Does Not Affect the Hypoxic Ventilatory Response or Systemic Arterial Blood Pressure Regulation During Hypoxia. Frontiers in Physiology, 9:655. doi: 10.3389/fphys.2018.00655. eCollection 2018.
Ogunbayo OA, Duan J, Xiong J, Wang Q, Feng X, Ma J, Zhu MX and Evans AM (2018).mTORC1 controls lysosomal Ca2+release through the two-pore channel TPC2. Science Signaling. 2018;11. doi: 10.1126/scisignal.aao5775.
Vara-Ciruelos, D., Dandapani, M., Gray, A., Agbani, E.O., Evans, A.M., Hardie, D.G. (2017). DNA damage by etoposide activates the α-1 isoform of AMP-activated protein kinase in the nucleus via the Ca2+/CaMKK2 pathway, enhancing human tumor cell survival. Revised and resubmitted to Molecular Cancer Research16, 345-357.
Moral-Sanz, J., Mahmoud, A.D., Ross, F.A., Eldstom, J., Fedida, D., Hardie D.G., Evans, A.M. (2016). AMP-activated protein kinase inhibits Kv1.5 channel currents of pulmonary arterial myocytes in response to hypoxia and inhibition of mitochondrial oxidative phosphorylation. J. Physiol., 594, 4901-4915.
Tarailo-Graovac M., Shyr C., Ross C.J., et al. (2016). Exome Sequencing and the Management of Neurometabolic Disorders. N. Engl. J. Med., 374, 2246-2255.
Mahmoud, A.D., Lewis, S., Juricic, L., Udoh, U.A., Hartmann, S., Jansen, M.A., Ogunbayo, O.A., Puggioni, P., Holmes, A.P., Kumar, P., Navarro-Dorado, J., Foretz, M., Viollet, B., Dutia, M.B., Marshall, I., Evans, A.M. (2015) AMP-activated protein kinase Deficiency Blocks the Hypoxic Ventilatory Response and Thus Precipitates Hypoventilation and Apnea. AJRCCM, 193, 1032-1043.
See also editorial by Gozal, D. (2016). The Energy Crisis Revisited: AMP-activated Protein Kinase and the Mammalian Hypoxic Ventilatory Response. AJRCCM 193, 945-946.
Skeffington, K.L., Higgins, J.S., Mahmoud, A.D., Evans, A.M., Sferruzzi-Perri, A.N., Fowden, A.L., Yung, H.W., Burton, G.J., Giussani, D.A., Moore, L.G. (2016). Hypoxia, AMPK activation and uterine artery vasoreactivity. J. Physiol., 594, 1357-1369.
Ogunbayo, O.A., Zhu, Y., Shen, B., Agbani, E., Li, J., Ma, J., Zhu, M.X., Evans, A.M. (2015). Organelle-specific Subunit Interactions of the Vertebrate Two-pore Channel Family. J. Biol. Chem., 290, 1086-1095.
Ikematsu, N., Dallas, M. L., Ross, F.A., Lewis, R.W., Rafferty, J.N., David, J.A., Suman, R., Peers, C., Hardie, D.G., Evans, A.M. (2011). Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability. PNAS USA, 108, 18132-18137.
Ross F.A., Rafferty J.N., Dallas M.L., Ogunbayo O., Ikematsu N., McClafferty H., Tian L., Widmer H., Rowe I.C., Wyatt C.N., Shipston M.J., Peers C., Hardie D.G., Evans A.M. (2011). Selective Expression in Carotid Body Type I Cells of a Single Splice Variant of the Large Conductance Calcium- and Voltage-activated Potassium Channel Confers Regulation by AMP-activated Protein Kinase. J. Biol. Chem., 286, 11929-11936.
Ogunbayo O.A., Zhu Y., Rossi D., Sorrentino V., Ma J., Zhu M.X., Evans A.M. (2011). Cyclic adenosine diphosphate ribose activates ryanodine receptors, whereas NAADP activates two-pore domain channels. J. Biol. Chem., 286, 9136-9140.
Clark, J.H., Kinnear, N.P., Kalujnaiab, S., Cramb, G., Fleischer, S., Jeyakumar, L.H., Wuytack, F., Evans, A.M. (2010). Identification of Functionally Segregated Sarcoplasmic Reticulum Calcium Stores in Pulmonary Arterial Smooth Muscle. J. Biol. Chem., 285, 13542-13549.
Calcraft, P.J., Arredouani, A., Ruas, M., Pan, Z., Cheng, X., Hao, X., Tang, J., Reindorf, K., Teboul, L., Chuang, K-T, Lin, P., Rui Xiao, R., Wang, C., Lin, Y., Wyatt, C.N., Parrington, J., Ma, J, Evans, A.M., Galione, A., Zhu, M.X. (2009). NAADP targets TPC2 to release Ca2+ from lysosomal stores in mammalian cells. Nature, 459, 596-600.