The main focus of my research is on understanding the structure-function relationships in ion channels activated by small molecules. These ligand-gated ion channels harness the energy provided by ligand binding to inter-convert between a number of functionally distinct conformations such as open, closed and desensitized states. I am trying to understand precisely how, in molecular terms, two classes of ligand-gated ion channel accomplish this. First, I am studying how the AMPA-type glutamate receptor responds to glutamate and various agonists and how this process is modulated by recently identified auxiliary proteins. I am also interested in how Acid Sensing ion channels (ASIC) couple the binding of multiple protons to channel activation and desensitization, both fundamental questions which are barely understood in this receptor type. To do this, I primarily use electrophysiology techniques such as whole cell and outside-out patch clamp recording combined with ultra-rapid perfusion systems and single channel recording. In addition, I use biochemical. computational and fluorescence approaches to advance our understanding of how these ion channels work.

 

PUBLICATIONS

Acid-sensing ion channels are tuned to follow high-frequency stimuli. MacLean DM and Jayaraman V (2016) J Physiol. 594: 2629–2645. PMID: 26931316

Dynamic membrane protein topological switching upon changes in lipid environment.
Vitrac, H, MacLean DM, Bogdanov, M, Jayaraman V, Dowhan, W.
(2015) PNAS. PMID: 26512118

A conserved structural mechanism of NMDA receptor inhibition: A comparison of ifenprodil and zinc.  Sirrieh RE, MacLean DM, Jayaraman V. (2015) J Gen. Physiol. 146(2):173-81.  PMC4516779

Subtype dependent NMDA receptor amino-terminal domain conformations and modulation by spermine. Sirrieh, R.E., MacLean, D.M., and Jayaraman, V. (2015) Journal of Biol. Chemistry. 290(20):1282-20.  PMC4432297

Stargazin promotes closure of the AMPA receptor ligand binding domain. MacLean, D.M., Ramaswamy, S., Du, M., Howe, J., and Jayaraman, V. (2014) Journal of General Physiology. 144(6):503-12.  PMC4242809

Constructing a rapid solution exchange system. MacLean, D.M. Ionotropic Glutamate Receptor Technologies, Dr. Gabriela Popescu, editor. Springer. (in press)

RNA based antagonist of NMDA receptors. Lee, G.*, MacLean, D.M.*, Ulrich, H., Zhao, X., Aronowski, J., Jayaraman, V. (2014) ACS Chemical Neuroscience 5(7):559-67.  PMC4102967

Proton mediated conformational changes in an Acid Sensing Ion Channel. Ramaswamy, S.S., MacLean, D.M., Gorfe, A.A., Jayaraman, V. (2013) Journal of Biol. Chemistry 288(50):35896-903.  PMC3861639

Amino-terminal domain tetramer organization and structural effects of zinc binding in the NMDA receptor. Sirrieh, R.E., MacLean, D.M., Jayaraman, V. (2013) Journal of Biol. Chemistry  288:22555-64.  PMC3829342

TARPs modulate AMPA receptor conformations before the gating transitions. MacLean, D.M. (2013) Journal of Physiology 591(Pt 7):1585-6.  PMC3624834

Role of conformational dynamics in AMPA receptor partial agonism. Ramaswamy, S.S., Cooper, D., Poddar, N., MacLean, D.M., Rambhandran, A.., Taylor, J.N., Uhm, H., Landes, C, Jayaraman, V. (2012) Journal of Biol. Chemistry 287(52):43557-64.  PMC3527942

Transmembrane AMPA receptor regulatory protein regulation of competitive antagonism: A problem of interpretation. MacLean, D.M., Bowie, D. (2011) Journal of Physiology 589(Pt 22):5383-90.  PMC3240879

Cations but not Anions regulate the responsiveness of Kainate receptor. MacLean, D.M., Wong, A.Y.C., Fay, A.M., Bowie, D. (2011) Journal of Neuroscience 31(6):2136-44.  PMID: 21307250

The d2 Glutamate-like receptor undergoes similar conformational changes as other Ionotropic Glutamate receptors. MacLean, D.M. (2009)  Journal of Neuroscience 29(21):6767-8. PMID: 19474303

Na+/Cl- dipole couples agonist binding to Kainate receptor activation. Wong, A.Y.C., MacLean, D.M., Bowie, D. (2007) Journal of Neuroscience 27(25):6800-9. PMID: 17581967

Ancestral reconstruction of the ligand binding pocket of Family C G-protein coupled receptors. Kuang, D., Chang, B., MacLean, D., Wang, M., Hampson, D.R. (2006) PNAS 103(38):14050-5.  PMC1563994

 

AWARDS

2016– K99/R00 Pathway to Independence Award, 2015-2020 NIH National Institute of Neurological Disorders and Stoke, Title: 3D structure and function of Acid Sensing Ion Channels

2015Paul F. Cranfield Student Award (Postdoctoral Category), Society of General Physiologists

2nd place Postdoctoral Fellow oral presentation, Annual BMB Graduate Program Spring Retreat

2014 –  1st place Postdoctoral Fellow oral presentation, Annual BMB Graduate Program Spring Retreat

2013 – American Heart Association Postdoctoral Fellowship, 2 Years

1st place Postdoctoral Fellow oral presentation, Annual BMB Graduate Program Spring Retreat

 


Education

Postdoctoral Fellow - UTH - Department of Biochemistry and Molecular Biology, Advisor:Vasanthi Jayaraman, 2012-present

PhD - McGill University, Department of Pharmacology and Therapeutics

HBSc - University of Toronto

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