Endogenous Homer Proteins Regulate Metabotropic Glutamate Receptor Signaling in Neurons

Abstract

Group I metabotropic glutamate receptors (mGluR1 and mGluR5) are important neuronal mediators of postsynaptic signaling that influence synaptic strength, plasticity, and other factors. Regulation of group I mGluR localization and function by Homer proteins appears to be a viable means for neurons to fine-tune these processes. The presence of different Homer isoforms can act as a switch to reprioritize mGluR1 and mGluR5 signaling at the point of IP(3) receptor activation by promoting or reducing activation of specific downstream effectors. Furthermore, these Homer-dependent effects on mGluR signaling may mechanistically underlie many of the long-term changes in neuronal function associated with changes in Homer protein expression described in the recent literature. However, most studies focusing on mGluR regulation by Homer proteins used relatively long-term overexpression. Thus, a definitive demonstration of mGluR1/5 signal regulation by natively expressed Homer proteins has been elusive. I examined the ability of endogenous Homer 1a to alter mGluR signaling in rat sympathetic neurons and hippocampal autapses using pituitary adenylate cyclase activating peptide (PACAP) to induce native Homer 1a expression. In sympathetic neurons, both Homer 1a overexpression and PACAP treatment reversed the decrease in mGluR1-mediated calcium current modulation associated with Homer 2b expression. In hippocampal autapses, PACAP treatment uncoupled postsynaptic mGluR5 from EPSC inhibition, similar to the effect of Homer 1a overexpression. In both cases, RNA silencing of Homer 1a but not control RNA interference treatment prevented the PACAP effect, suggesting that it resulted specifically from native Homer 1a expression.