The current report provides evidence for CNIH3 involvement in the pathophysiology of opioid dependence. CNIH3 encodes a small, highly conserved protein. The AMPA receptor core is formed by tetramers of the GluA1-4 subunits and up to four members of three protein groups: transmembrane AMPAR regulatory proteins (TARPs), cornichon homologs (CNIH3 and CNIH2), and the GSG1l protein.51 The receptor’s periphery contains transmembrane and other proteins [e.g., post-synaptic density protein 95 (PSD-95)] that bind with core proteins and each other in the postsynaptic density (PSD).51–54 CNIH2 and CNIH3 markedly slow AMPAR deactivation and desensitization in heterologous systems.54–56 One study54 suggested that the actions of CNIH2 and CNIH3 are selective for AMPARs containing GluA1 subunits; however, more recent reports51,57 do not support this specificity of binding. An investigation that focused on two hippocampal cell types with markedly different excitatory postsynaptic currents (EPSCs) implicated CNIH2 as largely responsible for the distinction between fast and slow EPSCs. Although this report did not examine whether CNIH3 plays a similar role, prior studies e.g., 55 have found that the two proteins have comparable effects on slowing AMPAR deactivation and desensitization.
