Professor Peter McNaughton, FMedSci
- Dr Joan Btesh/Postdoctoral researcher
- Dr David Cavalla/ Drug development
- Dr Christina Hanack/Postdoctoral researcher
- Dr Sergio Lainez /Postdoctoral researcher
- Dr Chun-Hsiang (Jackson) Tan/Postdoctoral researcher
- Dr Chris Tsantoulas/Postdoctoral researcher
- Dr Bruno Vilar/Postdoctoral researcher
- Miss Tamara Buijs
- Miss Victoria Swann
Peter McNaughton is Professor of Pharmacology and a member of the Wolfson Centre for Age-Related Research at King’s College London. His overall research theme is sensory systems – how do we detect the world around us, and how we know about the internal state of our own body? Current research projects focus on the following broad questions: How do we sense pain? What happens to pain sensation in chronic inflammation and following nerve injury – why does pain get worse? How do we sense warmth and cold? How do we sense our body temperature and how do we react in order to maintain body temperature constant? How do cells of the immune system “sniff out” and migrate towards areas of damage and pathogen invasion?
Pain is initiated when specific pain-sensitive nerve fibres (nociceptors) are activated by painful stimuli such as heat, strong mechanical stimuli and chemical stimuli. Examples of chemical stimuli include acid (e.g. from lemon juice) or capsaicin, the active ingredient of chilli peppers. In the last 10 years much progress has been made in understanding the cellular basis of pain, and in particular in isolating and characterising the membrane ion channels which open in response to these stimuli and thus initiate action potentials in primary pain-sensitive afferent nerve fibres. Our overall aim is to use a range of state-of-the-art cellular and molecular techniques to unravel an age-old problem which lies at the root of much human suffering.
Pain is unique amongst sensations in that it increases with prolonged exposure, a process known as sensitization, while in other sensory systems adaptation to a prolonged stimulus is observed. Sensitization has obvious protective value for the organism, but it is also responsible for much suffering in chronic pain states. Sensitization is caused by release of inflammatory mediators, such as bradykinin, prostaglandins and nerve growth factor (NGF), which bind to receptors on the neuronal cell membrane and activate cellular signalling pathways, which in turn modify the activity of downstream targets such as TRPV1 and HCN2.
We have recently become interested in how macrophages and neutrophils, cells of the immune system, are directed towards areas of damage or pathogen invasion, where they are needed to engulf pathogens and initiate tissue repair. We think that ion channels of the TRP family may be involved in this critical function.
We approach these questions about pain and thermal sensation using molecular and cellular techniques to find out about the proteins and cellular signalling systems that underlie sensation. We also use transgenic animals in which specific genes have been deleted to find out how particular genes influence pain and thermal sensation at the level of the whole animal. The main thrust of the work in our lab is basic science, but some of our discoveries have suggested novel “targets” for drugs effective against pain. We have started two drug discovery programmes aimed at developing novel analgesics which will inhibit these targets.
Peter McNaughton is a Fellow of the Academy of Medical Sciences and has published extensively in Nature, Science, Neuron, EMBO Journal, Journal of Neuroscience, Journal of Physiology and elsewhere (see selected publications below). He was Professor of Pharmacology and Head of the Department of Pharmacology at the University of Cambridge from 1999 until 2013, and he moved to the Wolfson Centre for Age-Related Research, King’s College London, on 1 Oct 2013. His work is currently funded mainly by the Medical Research Council (MRC), by the Biotechnology and Biological Sciences Research Council (BBSRC) and by the Wellcome Trust.
Current Research Interests
Major area 1: Involvement of HCN2 ion channels in inflammatory and neuropathic pain
Project 1: HCN ion channels and pain (BBSRC funded).
Neuropathic pain (pain caused by nerve injury) is abolished by deleting the ion channels HCN2 in a subset of sensory neurons. What are the special characteristics of these neurons?
Project 2: Role of HCN channels in neuropathic pain (MRC funded).
Can neuropathic pain be abolished long after initiation? We will use genetic and pharmacological approaches to investigate this question. With clinical colleagues we will investigate whether HCN ion channel blockers are effective in a volunteer model of neuropathic pain and in neuropathic pain patients.
Project 3: Small-molecule inhibitors of HCN2 (funded by Wellcome Trust Seeding Drug Discovery Initiative)
We are using medicinal chemistry in collaboration with an external company, Argenta, to develop HCN2 selective drugs as novel analgesics. We will then test these new drugs in animal models of pain.
Major area 2: The heat-sensitive ion channel TRPV1 as a target in inflammatory and neuropathic pain
Project 4: Novel analgesics based on AKAP79/TRPV1 antagonism (MRC funded). We have found that a scaffolding protein, AKAP79, interacts with a heat-sensitive ion channel, TRPV1, and that this interaction is important in pain. We will discover the structure of the binding site between TRPV1 and AKAP79, and we will use this structure to identify small-molecule “hits”. We will then test these hits in vivo and develop as novel drugs.
Major area 3: Genetic basis of abnormal pain sensation
Project 5: Genetic basis of abnormal pain (MRC funded)
With clinical colleagues we are identifying people with unusual pain syndromes. We will sequence their ion channels and identify the genetic abnormality. We will then study these ion channels using electrophysiology to find out how their properties differ from normal
Major area 4: Novel thermally-sensitive ion channels
Project 6: Ion channels controlling thermoregulation (BBSRC funded).
We have found that previously unknown thermally-sensitive ion channels are expressed in sensory neurons. We will sequence them and discover their molecular identity. We will then find out how these ion channels control the regulation of body temperature.
The main techniques in use in the lab are:
Patch clamp electrophysiology; Calcium imaging; Confocal microscopy; Fluorescence microscopy; Molecular biology; Immunohistochemistry; Cell culture; Creation of transgenic mouse strains; Animal behavioural experiments
Our work is funded by:
The Medical Research Council (MRC, UK): three project grants, total value £1.7m
The Biotechnology and Biological Sciences Research Council (BBSRC, UK): two project grants, one CASE PhD studentship, total value £900k
The Wellcome Trust (UK): drug development grant from Seeding Drug Discovery Initiative, value £4.4m.
Recent Selected Publications
Zhang, X, Huang, J. & McNaughton, P.A. (2005). NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO Journal 24, 4211 – 23
(N.B. This paper was featured in a Nature Research Highlights article in Nature, 438, pg. 893, 2005)
Vellani, V., Colucci, M., Lattanzi, R., Giannini, E., Negri, L., Melchiorri, P. and McNaughton, P.A. (2006) Sensitization of TRPV1 by the prokineticin receptor agonist Bv8. J. Neurosci. 26, 5109 – 16.
Huang, J., Zhang, X. and McNaughton, P.A. (2006) Modulation of temperature-sensitive TRP channels. Seminars in Cell and Developmental Biology 17, 638 – 45.
Cadiou, H., Studer, M., Jones, N.G., Smith, E. St. J., Ballard, A., McMahon, S.B. & McNaughton, P.A. (2007) Modulation of acid-sensing ion channel activity by nitric oxide. Journal of Neuroscience 27, 13251-13260.
Zhang, X., Li, L. & McNaughton, P.A. (2008) Pro-inflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150. Neuron 59, 450-461.
Momin A, Cadiou H, Mason A, & McNaughton PA (2008). Role of the hyperpolarization-activated current Ih in somatosensory neurons. J Physiol 586, 5911-5929.
Fan HC, Zhang X, & McNaughton PA (2009). Activation of the TRPV4 ion channel is enhanced by phosphorylation. J Biol Chem 284, 27884-27891.
Studer M & McNaughton PA (2010). Modulation of single-channel properties of TRPV1 by phosphorylation. J Physiol 588, 3743-3756.
Vellani V, Kinsey AM, Prandini M, Hechtfischer SC, Reeh P, Magherini PC, Giacomoni C, & McNaughton PA (2010). Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones. Mol Pain 6, 61.
Emery EC, Young GT, Berrocoso EM, Chen L, & McNaughton PA (2011). HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science 333, 1462-1466. (Listed as “Must read” on Faculty of 1000)
Vay L, Gu C, & McNaughton PA (2012). The thermo-TRP ion channel family: properties and therapeutic implications. British Journal of Pharmacology 165, 787–801.
Zhang, X., Mak, S., Li, L. Parra, A., Denlinger, B., Belmonte, C. & McNaughton, P.A. (2012) Direct inhibition of cold-activated ion channel TRPM8 by Gq. Nature Cell Biology 14, 850-858.
Emery E.C., Young G.T., McNaughton P.A. (2012) HCN2 ion channels: an emerging role as the pacemakers of pain. Trends Pharmacol Sci 33(8):456-463
Fischer M.J., Btesh, J & McNaughton, P.A. (2013) Disrupting sensitization of TRPV1 inhibits inflammatory hyperalgesia. J. Neurosci 33: 7407-7414. (Recommended on Faculty of 1000 Prime).
Btesh, J, Fischer M.J., Stott, K. & McNaughton, P.A. (2013) Mapping the binding site of TRPV1 on AKAP79: implications for inflammatory hyperalgesia. J. Neurosci 33: 9184-9193.
Young, G., Emery, E.C., Mooney, E.R., Tsantoulas, C. & McNaughton, P.A. (2014) Inflammatory and neuropathic pain are rapidly suppressed by peripheral block of hyperpolarisation-activated cyclic nucleotide-gated ion channels. Pain. 155:1708-19