Regulation of neuronal receptor function by receptor trafficking
Receptors residing on the plasma membrane sense extracellular signals, and translate the extracellular signals into intracellular electrical or chemical signals. The number of receptors on the plasma membrane is in part determined by the dynamic trafficking processes of these receptors. These trafficking processes include forward trafficking of receptors from the endoplasmic reticulum (ER) through Golgi apparatus to the plasma membrane, endocytosis of surface receptors, sorting of receptors following endocytosis, recycling of receptors back to the plasma membrane, and targeting receptors for degradation. For example, the dynamic trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is important for the expression of synaptic plasticity, a cellular model of learning and memory. Elucidating the detailed molecular mechanisms governing AMPA receptor trafficking will help us to better understand the underlying mechanisms of learning and memory in the brain.
Most of the receptor trafficking processes described above are dynamic, and optical imaging will provide the required spatial and temporal resolutions for examining the dynamic trafficking processes of different neuronal receptors. We plan to employ various optical imaging approaches, including total internal reflection fluorescent microscopy (TIF-FM) and two-photon microscopy, in combination with molecular, cellular, and biochemical techniques, to examine trafficking mechanisms of different neuronal receptors in detail. Our goal is to understand how the trafficking mechanisms of these receptors impact their function in neurons, and to target the trafficking mechanisms of different neuronal receptors as potential therapeutic strategies for human diseases involving these receptors.
Principal Invesigator: Da-Ting Lin, Ph.D., Assistant Professor
Associate Research Scientist: Yun Li, Ph.D.
Postdoc Associate: Lifeng Zhang, Ph.D.
Predoc Associate: Wei Wang, M.S.
Research Administrative Assistant: Tonnya Norwood, B.S.
Li Y, Roy BD, Wang W, Zhang L, Sampson SB, Yang Y, Lin DT. 2012. Identification of two functionally distinct endosomal recycling pathways for dopamine d2 receptor. J Neurosci 32(21):7178-7180.
Li Y, Roy BD, Wang W, Zhang LF, Sampson SB, Lin DT. 2012. Imaging pHluorin tagged receptor insertion to the plasma membrane in primary cultured mouse neurons. J Vis Exp e4450.
Zhang LF, Lapierre A, Roy BD, Lim M, Zhu J, Sampson SB, Yun K, Lyons B, Li Y, Lin DT. 2012. Imaging glioma initiation in vivo through a polished and reinforced thin-skull cranial window. J Vis Exp e4201.
Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, Massicotte C, Henrion E, Diallo O, S2D Group, Shekarabi M, Marineau C, Shevell M, Maranda B, Mitchell G, Nadeau A, D'Anjou G, Vanasse M, Srour M, Lafrenière RG, Drapeau P, Lacaille JC, Kim E, Lee JR, Igarashi K, Huganir RL, Rouleau GA, Michaud JL. 2011. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet 88(3):306-316. PMC3059427
Araki Y, Lin DT, Huganir RL. (2010) Plasma membrane insertion of the AMPA receptor GluA2 subunit is regulated by NSF binding and Q/R editing of the ion pore. PNAS USA 107(24):11080-11085. PMC2890737
Mao L, Takamiya K, Thomas G, Lin DT, Huganir RL. 2010. GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions. Proc Natl Acad Sci USA 197(44):19038-19043. PMCID: PMC2973854 PMC2973854
Lin, D.T., Makino, Y., Sharma, K., Hayashi, T., Neve, R., Takamiya, K., and Huganir, R.L. (2009) Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation. Nature Neuroscience 12(7): 879-887. DOI: 10.1038/nn.2351.
Thomas, G.M, Lin, D.T., Nuriya, M., and Huganir, R.L. (2008) Rapid and bidirectional regulation of AMPA receptor phosphorylation and trafficking by JNK. The EMBO Journal 27(2): 361-72.
Lin, D.T. and Huganir, R.L. (2007) PICK1 and Phosphorylation of the Glutamate Receptor 2 (GluR2) AMPA Receptor Subunit Regulates GluR2 Recycling after NMDA Receptor-Induced Internalization. Journal of Neuroscience 27 (50): 13903-13908.
Lin, D.T. *, Wu, J. *, Holstein, D., Upadhayay, G., Rourk, W., Muller, E. and Lechleiter, J.D. (2007) Ca2+ signaling, mitochondria and sensitivity to oxidative stress in aging astrocytes. Neurobiology of Aging 28: 99-111 (*equal contribution to the work).
Wu, J., Holstein, D.J., Upadhyay, G., Lin, D.T., Conway, S., Muller, E. and Lechleiter, J.D. (2007) Purinergic Receptor Stimulated IP3-Mediated Ca2+Release Enhances Neuroprotection by Increasing Astrocyte Mitochondrial Metabolism During Aging. Journal of Neuroscience 27(24):6510-6520.
Beique, J-C.*, Lin, D.T.*, Kang, M.G., Aizawa H., Takamiya K., and Huganir, R.L. (2006) Synapse-specific regulation of AMPA receptor function by PSD-95. P.N.A.S. USA 103: 19535-19540 (* equal contribution to the work).
Lechleiter, J.D., Lin, D.T., and Sieneart, I. (2002) Multi-Photon Laser Scanning Microscopy Using An Acoustic Optical Deflector (AOD). Biophys. J. 83(4): 2292-2299.
Lin, D.T. and Lechleiter, J.D. (2002) Mitochondrial Targeted Cyclophilin D Protects Cells from Cell Death By Peptidyl Prolyl Isomerication. JBC 277 (34): 31134-31141.