RGS14 is a multifunctional signaling protein that integrates G protein, MAPkinase, and calcium/CaM signaling pathways. RGS14 is found in brain where it is highly enriched in dendrites and spines of pyramidal neurons in hippocampal region CA2. We discovered that RGS14 is critically important as a natural suppressor of synaptic plasticity (long-term potentiation, LTP) in CA2 neurons. Our studies show that ectopic delivery of RGS14 to CA1 neurons where RGS14 is not expressed blocks LTP there, suggesting that RGS14 engages common signaling pathways that are critical for synaptic plasticity in both populations of neurons. Unlike CA1 neurons, little is known about CA2 neurons where RGS14 is expressed. This enigmatic brain region has been implicated in social behavior and human neuro-psychological diseases including schizophrenia, the autism/bipolar disorders, and epilepsy. Remarkably, we have found that mice lacking RGS14 (RGS14-KO) exhibit an unexpected enhancement of spatial learning and object recognition memory compared with wild type littermates, with no differences in non-hippocampal-dependent behaviors. Furthermore, RGS14-KO mice expressed a surprisingly robust nascent LTP with enhanced neuronal excitability at glutamatergic synapses in CA2, with no impact on plasticity in adjacent CA1 neurons. Together, these findings highlight the importance of understanding the molecular mechanism(s) whereby RGS14 regulates LTP and synaptic plasticity within CA2 hippocampal neurons. LTP and associated spine plasticity depends on a rise in postsynaptic calcium due to glutamate activation of NMDA/GluN channels and the voltage-gated calcium channel Cav1.2, which result in activation of CaM and CaMKII signaling pathways. These pathways, in turn, increase actomyosin-driven trafficking and insertion of AMPA/GluA receptor vesicles at the synapse that result in increased spine size (i.e. structural plasticity). Of note, we find that RGS14 suppresses the activity-induced rise in spine calcium, inhibits Cav1.2, binds Ca++/CaM, and is phosphorylated by CaMKII. Furthermore, we find that RGS14 suppresses spine structural plasticity associated with LTP, and exists in brain as part of a high-molecular weight complex enriched with spine myosins (MyoV, MyoVI, MyoII) and actin binding proteins. Based on these observations, our working hypothesis is that RGS14 suppresses spine calcium by inhibiting Cav1.2 channels, and blocks LTP by engaging the actomyosin system (in a regulated way) to limit surface AMPA receptors. We further propose that these actions of RGS14 are regulated by its binding partners CaM, CaMKII, H-Ras/Rap2-GTP and Gai1. To test these ideas, we propose the following experiments.
AIM 1. Determine how Ca++/CaM binding and CaMKII phosphorylation modulate established RGS14 functions.
AIM 2 : Determine how RGS14 regulates Cav1.2 and suppresses postsynaptic calcium signaling in hippocampal neurons.
AIM 3 : Determine how RGS14 impacts AMPA receptor recycling and engages the actomyosin system to suppress spine plasticity in hippocampal neurons.

Public Health Relevance

These studies will define novel molecular mechanisms that underlie normal physiological processes such as learning and memory that are altered in human disease states such as schizophrenia or the autism and bipolar spectrum of disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037112-20
Application #
9978961
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Churn, Severn Borden
Project Start
1997-12-01
Project End
2024-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
20
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Gerber, Kyle J; Squires, Katherine E; Hepler, John R (2018) 14-3-3? binds regulator of G protein signaling 14 (RGS14) at distinct sites to inhibit the RGS14:G?i-AlF4- signaling complex and RGS14 nuclear localization. J Biol Chem 293:14616-14631
Squires, Katherine E; Gerber, Kyle J; Pare, Jean-Francois et al. (2018) Regulator of G protein signaling 14 (RGS14) is expressed pre- and postsynaptically in neurons of hippocampus, basal ganglia, and amygdala of monkey and human brain. Brain Struct Funct 223:233-253
Squires, Katherine E; MontaƱez-Miranda, Carolina; Pandya, Rushika R et al. (2018) Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease. Pharmacol Rev 70:446-474
Evans, Paul R; Gerber, Kyle J; Dammer, Eric B et al. (2018) Interactome Analysis Reveals Regulator of G Protein Signaling 14 (RGS14) is a Novel Calcium/Calmodulin (Ca2+/CaM) and CaM Kinase II (CaMKII) Binding Partner. J Proteome Res 17:1700-1711
Zou, Juan; Salarian, Mani; Chen, Yanyi et al. (2017) Direct visualization of interaction between calmodulin and connexin45. Biochem J 474:4035-4051
Branch, Mary Rose; Hepler, John R (2017) Endogenous RGS14 is a cytoplasmic-nuclear shuttling protein that localizes to juxtanuclear membranes and chromatin-rich regions of the nucleus. PLoS One 12:e0184497
Gerber, Kyle J; Squires, Katherine E; Hepler, John R (2016) Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity. Mol Pharmacol 89:273-86
Brown, Nicole E; Lambert, Nevin A; Hepler, John R (2016) RGS14 regulates the lifetime of G?-GTP signaling but does not prolong G?? signaling following receptor activation in live cells. Pharmacol Res Perspect 4:e00249
Brown, Nicole E; Goswami, Devrishi; Branch, Mary Rose et al. (2015) Integration of G protein ? (G?) signaling by the regulator of G protein signaling 14 (RGS14). J Biol Chem 290:9037-49
Brown, Nicole E; Blumer, Joe B; Hepler, John R (2015) Bioluminescence resonance energy transfer to detect protein-protein interactions in live cells. Methods Mol Biol 1278:457-65

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