Activity Dependent Inhibition of AMPA Receptors by Zn2+

• DOI: 10.1523/jneurosci.1481-20.2020
• Publication Date: 2020-10-12T22:25:14Z
• Authors: Elisa Carrillo; Nidhi K. Bhatia; Askar M. Akimzhanov; Vasanthi Jayaraman
• Keywords: Homomeric; Kainate receptor; Synaptic cleft

Zn 2+ has been shown to have a wide range of modulatory effects on neuronal AMPARs. However, the mechanism modulation is largely unknown. Here we show that inhibits GluA2(Q) homomeric receptors in an activity- and voltage-dependent manner, indicating pore block mechanism. The rate inhibition slow, hundreds milliseconds at millimolar concentrations; hence, only observed residual nondesensitizing currents. Consequently, higher for GluA2 complex with auxiliary subunits γ2 γ8 where activation larger. extent also dependent charge site 607, undergoes RNA editing replacing glutamine arginine, percent being lower IC 50 edited GluA2(R) relative unedited GluA2(Q607E), mutation genetic screen patient exhibiting developmental delays. We significant during rapid repetitive activity pulses concentrations glutamate both expressed HEK cells as well native cortical neurons C57BL/6J mice either sex, physiological relevance this inhibition. SIGNIFICANCE STATEMENT present along synaptic vesicles coreleased transmission, modulating postsynaptic ionotropic receptors. While NMDA subtype characterized, AMPA much less known. systematically studied AMPARs by varying calcium permeability, subunits, levels activity-dependent opening up pathway means pharmacologically modulate