RGS14 is a newly appreciated effector protein that integrates G protein and H- Ras/Raf1/ERK signaling pathways. RGS14 is a brain protein that is highly enriched in and largely restricted in its expression pattern to dendrites and spines of neurons of hippocampal region CA2. We recently discovered that RGS14 is critically important as a natural suppressor of synaptic plasticity (LTP) in CA2 neurons. Furthermore, we show that ectopic expression of RGS14 in CA1 neurons where RGS14 is not expressed blocks LTP there, suggesting that RGS14 engages common cell signaling pathways critical for synaptic plasticity. Unlike the well-studied CA1 region, very little is known about CA2 neurons or RGS14 there. The CA2 is implicated in human neurological diseases including schizophrenia, the autism/bipolar spectrum of disorders, and epilepsy. Mice lacking RGS14 (RGS14-KO) exhibit a marked and unexpected enhancement in spatial learning and object recognition memory compared with wild type littermates, but show no differences in non- hippocampal-dependent behaviors. RGS14-KO mice also exhibit 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 neuronal/synaptic plasticity. Within CA2/CA1 neurons, LTP expression and its suppression is due to both Ca++-dependent (CaM, CaMKII) and Ca++-independent (ERK, cAMP/PKA) mechanisms. RGS14 binds inactive G?i1/3-GDP and active H-Ras-GTP to form a heterotrimeric signaling complex that integrates G protein and MAPK signaling pathways. RGS14 also binds calmodulin (CaM) in a Ca++-dependent manner. These findings suggest RGS14 is well positioned to regulate plasticity in host neurons. Consistent with this idea, the nascent LTP in CA2 neurons following loss of RGS14 is dependent on MEK/ERK signaling. Based on this, my working hypothesis is that the G?i-GDP:RGS14:H-Ras-GTP signaling complex integrates G protein, MAPK and Ca++/CaM signaling pathways to serve as a natural suppressor of synaptic plasticity in host neurons. However, the molecular/structural basis for how RGS14 binds G proteins, H-Ras and CaM to operate as a signaling switch/integrator is unknown. Furthermore, the dynamic subcellular localization and regulation of native RGS14 in its natural host CA2 neurons, and the signaling pathways that the G?i1:RGS14: H-Ras signaling complex engages to regulate synaptic plasticity in host CA2/CA1 is entirely unknown.
The Specific Aims are:
AIM 1. Determine the structural basis and interdomain dynamics for how RGS14, G?i, H-Ras and CaM interact to form a functional signaling complex.
AIM 2 : Determine the cellular properties of native RGS14 and how RGS14 engages the H-Ras/ERK signaling pathway to regulate synaptic plastic in natural host CA2 neurons.
AIM 3 : Determine the signaling pathways used by the G?i:RGS14: H- Ras complex in CA2 or CA1 hippocampal neurons to regulate LTP in hippocampal slice preparations.

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Stewart, Randall R
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Emory University
Schools of Medicine
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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
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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
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
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; 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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