John Marshall, Ph.D., Cambridge University, 1989Edit My Page
In response to hormonal or synaptic stimulation, excitable cells (including smooth muscle, cardiac muscle, and neurons) undergo a diversity of changes in their electrical properties. My lab is studying the trafficking and localization of glutamate receptors and calcium channels to synapses, and their modulation by protein kinases.
A major focus of our research is regulation of glutamate receptors that play key roles in neuronal communication. Failure to regulate these receptors can cause seizure disorders and neurodegeneration such as, Alzheimer's, Huntington's and Parkinson's disease. We have identified proteins that control the movement and localization of these receptors at synapses with the aim of designing drugs that prevent neuronal death in disease states. We also study the mechanisms by which growth factors, such as IGF 1, promote neuronal development. Our work demonstrates that growth factors enhance the activity of L-type calcium channels to regulate dendritic branching, spine formation, and long-term survival.
I became interested in this line of research because I was interested in processes such as learning and memory. Receptors are key elements in the communication of neurons and by studying them we hope to understand at the molecular level how the brain functions.
Changes in channel activity are known to regulate neuronal gene expression, cell death, and communication. Glutamate receptors play key roles in certain forms of synaptic plasticity, and the failure to regulate these receptors can cause seizure disorders and neurodegenerative disease. We use molecular biological and patch-clamp techniques to study glutamate receptors in neurons to determine how their properties are modulated by kinases, such as CaM-Kinase II. My lab has mainly been studying kainate type of glutamate receptors. We are interested in the trafficking and localization of kainate receptors to pre- and post-synaptic sites. We have found that the MAGUK (membrane-associated guanylate kinase) family of postsynaptic density (PSD) proteins can mediate kainate receptor clustering and anchoring at the membrane surface by binding the intracellular C-terminal tails of the receptors. Additionally, the same molecules provide a scaffold for the assembly of transduction complexes, thus coupling kainate receptors to downstream signaling processes.
Calcium influx through the related L-type calcium channels, CaV1.2 and CaV1.3, performs an array of functions that include promoting neuronal survival, controlling calcium signaling to the nucleus, influencing the rate of neurite outgrowth, stabilizing dendritic arbors (Marshall et al., 2003; Gao et al., 2006). We have shown that the growth factor, insulin-like growth factor 1 (IGF-1) rapidly potentiates neuronal CaV1.2 channel activity via an IGF-1 receptor tyrosine kinase- (RTK-), PI-3 kinase- and Akt-dependent pathway that culminates in Src-dependent phosphorylation of a specific tyrosine residue on CaV1.2 (Blair and Marshall, 1997; Blair et al., 1999; Bence-Hanulec et al., 2000). In the long-term, IGF-1 and CaV1.2 have been shown to promote neuronal survival via regulation of specific transcription factors, including CREB. We recently found that CaV1.3 channel activity is also rapidly potentiated by IGF-1, and that, unlike the IGF-1 regulation of CaV1.2, the CaV1.3 signaling pathway involves IP3-sensitive stores, CaMKII, and phosphorylation of the CaV1.3 EF hand motif. Mechanistically, we find that the potentiation arises from increased activation of CaV1.3 at hyperpolarized membrane potentials and, within minutes, produces increased levels of phospho-CREB, a transcription factor strongly associated with promoting dendritic development and neuronal survival. We additionally found that CaV1.3 modulation is dependent on the scaffold proteins Shank and Homer. Shank binds to the C-terminus of CaV1.3a to recruit Homer and tether CaV1.3 to IP3-sensitive stores.
1995-1998 Upjohn Assistant Professor of Pharmacology
1993-1994 American Heart Fellowship
2000-2003 American Heart Established Investigator Award
2003-present Member, MBL Neuroscience Institute and Neuroimaging group
2003, 2004 Albert and Ellen Grass Faculty Award
2003-present NIH Study Section Reviewer
The Society for Neuroscience
NIH. (PI) Marshall, J.; R01 NS39309-04; "Modulation and Targeting of Kainate Receptors"; 9/15/2001-7/31/2005.
Award Amount $150,000 (Direct costs in current year).
NIH. (PI) Marshall, J.; R01 NS39063-04; "Mechanism of L-Channel Mediated Neuronal Survival"; 5/15/2001-4/30/2006 (no-cost extension).
Award Amount $200,000 (Direct costs in current year).
NIH. (PI) Blair, L., (Co-PI) Marshall, J.; R01 NS37676-04; "Modulation of Neuronal Calcium Channels by IGF-1"; 04/06/1999-03/31/2005 (no-cost extension).
Award Amount $137,264 (Direct costs in current year).
NIH. (PI) Mierke, D., (Co-PI) Marshall, J.; R21DA015173-02; "Drug Design: Glutamate Receptor Signaling"; 4/1/2002-3/31/2005 (no-cost extension).
Award Amount $100,000 (Direct costs in current year).
NIH. (PI) Mierke, D., (Co-PI) Marshall, J.; R01 DA018428-01; "Drug Design: Glutamate Receptor Signaling"; 8/1/2004-7/31/2009.
Award Amount $225,000 (Direct costs in current year).
NIH. (PI) Marshall, J.; "Regulation of Kainate Receptor Trafficking"; 12/01/200511/30/2010.
Award Amount $307,152 (Direct Costs in year 1).
Albert and Ellen Grass Faculty Award (2005, $50,000).
1991-1993 Neurobiology course, Woods Hole.
1995-1996 Brown University, Physiology course (120 students)
1995-1998 Brown University, Director Medical School Pharmacology course (70 students)
1998-2000 Medical School Neuropharmacology lectures (70 students)
1998- present Brown University, Physiological Pharmacology- BIO 126 (Pharmacology course, 35-80 students, I give about 25 (90 minute) lectures. A short list of the most common medically prescribed drugs will be discussed in terms of their fundamental modes of action and clinical importance e.g. the electrophysiology of the heart is discussed as a background to anti-arrhythmic drugs. A major focus of this course is signal transduction pathways and molecular biology of neurodegenerative diseases e.g. neurotrophic factors and the treatment of nerve disease (Motor neuron, Parkinson's), pathogenesis of Alzheimer's disease, Stem cell transplantation. Students are introduced to increasingly important aspects of treatments such as recombinant DNA techniques and gene therapy.
2002 Signal transduction, Receptors, Protein structure, and Synapses - Bio 217. A graduate level course that trains students in the basics of signaling pathways, receptor binding theory, protein structure, basic electrophysiology of ion channels and synaptic plasticity (LTP/LTD).
- Advanced Cellular and Molecular Neurobiology (BN0204)
- Physiological Pharmacology (BI0126)
- Receptors, Channels and Signaling (BI0217)
- Piserchio, A., Spaller, M., Marshall, J., and Mierke, D.F (2004) Targeting specific PDZ domains of PSD-95: Structural basis for enhanced affinity and enzymatic stability of a cyclic peptide Chemistry&Biology 11, 468-473.(2004)
- Ren, Z., Riley, N., Needleman, L., Sanders JM, Swanson GT, Marshall J. (2003) Cell surface expression of GluR5 kainate receptors is regulated by an endoplasmic reticulum retention. J. Biol. Chem. 26;278(52):52700-9.(2003)
- Marshall J, Dolan BM, Garcia EP, Sathe S, Tang X, Mao Z, Blair L.A.C. (2003) Calcium channel and NMDA receptor activity differentially regulate nuclear C/EBP levels to control neuronal survival. Neuron 39: 625-629.(2003)