expected. Remarkably, however, co-expression of γ-8 and CNIH-2 with GluA1A2 heteromers reversed CNIH-2-induced slowing (Figure 6C). Together these findings are of considerable interest for two main reasons. One, such data are consistent with a model in which γ-8 prevents the physical interaction of CNIH with non-GluA1 subunits, thus explaining the observed CNIH subunit specificity. And two, when CNIH-2 is bound to GluA1 but prevented from functionally interacting with GluA2 by γ-8, as would be expected in neurons, CNIH-2 has little influence on the kinetics of GluA1A2 heteromers. It is important to note that previous efforts to understand CNIH function have focused heavily on whether or not CNIH proteins are associated with synaptic AMPARs or sequestered in the ER. The present data appear to diminish the relevance of this issue owing to the fact that all of the physiological consequences of deleting CNIH proteins can be explained by the selective loss of synaptic GluA1A2 heteromers.
