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Calcium-permeable AMPA receptors containing Q/R-unedited GluR2 direct human neural progenitor cell differentiation to neurons

Nicholas P. Whitney^*,,, Hui Peng^*,,, Nathan B. Erdmann^*,,, Changhai Tian^*,,, Daniel T. Monaghan and Jialin C. Zheng^*,,,,1

^* Laboratory of Neurotoxicology,

Center for Neurovirology and Neurodegenerative Disorders,

Department of Pharmacology and Experimental Neuroscience, and

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska

¹Correspondence: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center, Omaha, NE 68198-5800, USA. E-mail: jzheng{at}unmc.edu

We identify calcium-permeable -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on human neural progenitor cells (NPCs) and present a physiological role in neurogenesis. RNA editing of the GluR2 subunit at the Q/R site is responsible for making most AMPA receptors impermeable to calcium. Because a single-point mutation could eliminate the need for editing at the Q/R site and Q/R-unedited GluR2 exists during embryogenesis, the Q/R-unedited GluR2 subunit presumably has some important actions early in development. Using calcium imaging, we found that NPCs contain calcium-permeable AMPA receptors, whereas NPCs differentiated to neurons and astrocytes express calcium-impermeable AMPA receptors. We utilized reverse-transcription polymerase chain reaction and BbvI digestion to demonstrate that NPCs contain Q/R-unedited GluR2, and differentiated cells contain Q/R-edited GluR2 subunits. This is consistent with the observation that the nuclear enzyme responsible for Q/R-editing, adenosine deaminase (ADAR2), is increased during differentiation. Activation of calcium-permeable AMPA receptors induces NPCs to differentiate to the neuronal lineage and increases dendritic arbor formation in NPCs differentiated to neurons. AMPA-induced differentiation of NPCs to neurons is abrogated by overexpression of ADAR2 in NPCs. This elucidates the role of AMPA receptors as inductors of neurogenesis and provides a possible explanation for why the Q/R editing process exists.—Whitney, N. P., Peng, H., Erdmann, N. B., Tian, C., Monaghan, D. T., Zheng, J. C. Calcium-permeable AMPA receptors containing Q/R-unedited GluR2 direct human neural progenitor cell differentiation to neurons.

Key Words: glutamate • Q/R editing • neurogenesis • dendritic arborization • ADAR2