Local second messenger signalling in synaptic plasticity
Matthew G. Gold, PhD
Biosciences Research Fellow
Affiliated with the Institute of Structural and Molecular Biology
Tel: +44 (0)20 7679 7161
Mr. Ryan Walker-Gray, UCL Overseas Research Scholar PhD Student
Miss Neha Patel, UCL Biosciences MRes student
Dr Matthew Gold graduated with a degree in Natural Sciences from the University of Cambridge in 2003. He completed his PhD with Professor David Barford FRS in the Department of Structural Biology at the Institute of Cancer Research in 2007. He was a Sir Henry Wellcome Fellow with Professor John Scott FRS (University of Washington, Dept. Pharmacology) and Professor Annette Dolphin (UCL, Dept. NPP) prior to starting his own research group at UCL in 2012.
Changes in synaptic strength (synaptic plasticity) following synaptic transmission are thought to underlie memory formation. Synaptic plasticity is mediated by signalling enzymes on either side of the synaptic cleft that respond to changes in second messenger concentration following synaptic transmission. We are interested in resolving fundamental mechanisms that involve the action of second messengers. Questions we aim to address include:
- How does cAMP-dependent protein kinase (PKA) mediate different forms of synaptic plasticity?
- How can postsynaptic entry of the same second messenger (Ca2+) lead to opposite effects on synaptic strength?
To understand how the same second messenger can have different cellular effects, and to accurately identify critical substrates of second messenger-sensitive enzymes, it is important to consider that the action of second messengers is localised within cells. Anchoring proteins position second messenger-sensitive enzymes with their substrates at subcellular locations where second messenger concentrations are periodically elevated. For example, in the case of cAMP signalling, cAMP-dependent protein kinase (PKA) is positioned in proximity to its substrates and to adenylyl cyclases by A-Kinase Anchoring Proteins (AKAPs). We are taking a multidisciplinary approach to investigate local second messenger signalling mechanisms. We study the structure of macromolecular complexes involved in local second messenger signalling using high-resolution approaches from structural biology. This strand of research is exemplified by studies of the AKAP79 complex (below). We are also developing novel technologies, using synthetic and chemical biology, for identifying the AKAPs and PKA substrates associated with different physiological processes driven by cAMP, with an emphasis on synaptic plasticity. Following this approach, we hope to illuminate both normal and pathological synaptic biology.
Structure of the postsynaptic AKAP79 signalling complex. AKAP79 is an A-Kinase Anchoring Protein that anchors PKA in tandem with the Ca2+-sensitive phosphatase calcineurin in proximity to Ca2+ entry sites. AKAP79 directs both PKA and calcineurin to regulate the phosphorylation state of postsynaptic ion channels including AMPA-type glutamate receptors.
Gold, M. G., Fowler, D. M., Means, C. K., Pawson, C. T., Stephany, J. J., Langeberg, L. K., Fields, S., Scott, J. D. (2013). Engineering A-kinase anchoring protein (AKAP)-selective regulatory subunits of protein kinase A (PKA) through structure-based phage selection. JBC, 288, 17111-17121.
Gold, M. G., Gonen, T., & Scott, J. D. (2013). Local cAMP signaling in disease at a glance. J Cell Sci, 126, 4537-4543.
Gold, M.G. (2012) Solving the structure of the postsynaptic density: A frontier in the understanding of synaptic plasticity. BioEssays, 34, 599-608.
Gold, M.G., Reichow, S.L., O’Neill, S., Weisbrod, C.R., Langebreg, L.K., Bruce. J.E., Gonen, T., Scott, J.D. (2012) AKAP2 anchors PKA with aquaporin-0 to support ocular lens transparency. EMBO Mol Med, 4, 15-26.
Gold, M.G., Stengel, F., Nygren, P.J., Weisbrod, C.R., Bruce, J.E., Robinson, C.V., Barford, D., and Scott, J.D. (2011) Architecture and dynamics of an A-kinase anchoring protein 79 (AKAP79) signaling complex. PNAS, 108, 6426-6431.
Gold, M.G., Lygren, B., Dokurno, P., Hoshi, N., McConnachie, G., Tasken, K., Carlson, C.R., Scott, J.D. and Barford, D. (2006) Molecular Basis of AKAP specificity for PKA regulatory subunits. Mol Cell, 24, 383-393.