Characterizing a Novel RGS14:MyosinV/VI Interaction in Brain

Abstract

RGS14 is a complex multifunctional signaling protein that integrates G protein, Ras/ERK and Ca++/CaM/CaMKII signaling pathways. The protein is composed of an RGS domain that binds active Gαi/o, two tandem Ras/Rap binding domains (R1, R2) which bind active H‐Ras‐GTP and Rap2A‐GTP to regulate MAP kinase signaling, a G protein regulatory (GPR) motif that binds inactive Gαi1/3, and a Ca++/CaM binding site. RGS14 is highly expressed in the hippocampus, the brain center for learning and memory, which is composed of areas CA3, CA2, and CA1. Schaffer collateral (SC) projections from CA3 to CA1 display long term potentiation (LTP), a stable potentiation in post‐synaptic strength in response to brief periods of synaptic stimulation such as during learning in animals. Within the hippocampus RGS14 is highly expressed in postsynaptic dendrites and spines of area CA2, where SC inputs from CA3 to CA2 neurons show a surprising resistance to LTP. CA2 has been shown to be important for social learning and memory, and we have shown that RGS14 is a natural suppressor of LTP and synaptic plasticity in this area. That is, loss of RGS14 in CA2 (RGS14‐KO) restores synaptic plasticity (LTP) in CA2 and markedly enhances hippocampal learning. However, it remains unknown how RGS14 interacts with other signaling proteins to regulate synaptic plasticity. In proteomic studies, RGS14 recovered from mouse brain by immunoprecipitation was subjected to mass spectrometry and proteomic analysis, showing its association with a high molecular‐weight protein complex including actin‐based myosin motor proteins (Myosin V, Myosin VI and Myosin II) and their regulatory proteins, among others. MyoV is involved in activity‐dependent insertion of AMPA glutamate receptor subunits (GluR1, GluR2) and NMDA receptors, regulation of calcium and proper positioning of calcium intracellular stores. MyoVI is enriched at the postsynaptic density where it regulates AMPA receptor recycling. These myosin classes have crucial roles in regulating synaptic plasticity and LTP. Follow up studies have shown RGS14 in complex with MyoV and MyoVI in whole brain lysates. However, it remains unclear how RGS14 interacts with MyoV/VI to regulate synaptic plasticity. Ongoing studies will determine if RGS14 binds directly or indirectly to MyoV/VI and how that is regulated, as well as elucidate the physiological function of this interaction, thereby providing insight into the functions of both RGS14 and MyoV/VI in their roles in modulating synaptic plasticity and hippocampal‐dependent learning and memory.Support or Funding InformationThis research was supported by grants NIH/NINDS to JRH (5R01NS37112 and 1R21NS074975), and in part by the Emory Neuroscience NINDS Core Facilities and NIH/NINDS under award number P30NS055077.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.