Model for gp95/120-induced activity-dependent synaptic hyperexcitation.

<p>Both FIV gp95 and HIV gp120 stimulate CXCR4 and NMDARs, inducing activity-dependent synaptic dysfunction via cGKII activation. The gp95/120 stimulation of NMDARs activates nNOS, production of NO, leading to activation of soluble guanylyl cyclase and the production of cGMP, which in turn activates cGKII. Both the production of IP3 by the gp95/120 stimulation of CXCR4 and cGKII-induced phosphorylation of IP3Rs enhance ER Ca²⁺ release, contributing to Ca²⁺ hyperactivity. In addition, gp95-induced cGKII activation increases GluA1 phosphorylation, promoting elevation of surface AMPARs, which leads to the elevation of synaptic excitation. Therefore, the gp120/gp95-induced stimulation of cGKII is critical for synaptic hyperexcitation in HAND pathophysiology. AMD3100, bicyclam derivative plerixafor hydrochloride; AMPAR, AMPA receptor; cGKII, cGMP-dependent protein kinase II; cGMP, cyclic GMP; CNQX, 6-Cyano-7-nitroquinoxaline-2,3-dione; ER, endoplasmic reticulum; FIV, feline immunodeficiency virus; HAND, HIV-associated neurocognitive disorder; HIV, human immunodeficiency virus; IP3R, inositol triphosphate receptor; NMDAR, NMDA receptor; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; NPA, <i>N</i>^ω-Propyl-L-arginine hydrochloride; PSD95, postsynaptic density 95.