Abstract
The regulator of G-protein signaling 14 (RGS14) is a multifunctional signaling protein that regulates post synaptic plasticity in neurons. RGS14 is expressed in the brain regions essential for learning, memory, emotion, and stimulus-induced behaviors, including the basal ganglia, limbic system, and cortex. Behaviorally, RGS14 regulates spatial and object memory, female-specific responses to cued fear conditioning, and environmental- and psychostimulant-induced locomotion. At the cellular level, RGS14 acts as a scaffolding protein that integrates G protein, Ras/ERK, and calcium/calmodulin signaling pathways essential for spine plasticity and cell signaling, allowing RGS14 to naturally suppress long-term potentiation (LTP) and structural plasticity in hippocampal area CA2 pyramidal cells. Recent proteomics findings indicate that RGS14 also engages the actomyosin system in the brain, perhaps to impact spine morphogenesis. Of note, RGS14 is also a nucleocytoplasmic shuttling protein, where its role in the nucleus remains uncertain. Balanced nuclear import/export and dendritic spine localization are likely essential for RGS14 neuronal functions as a regulator of synaptic plasticity. Supporting this idea, human genetic variants disrupting RGS14 localization also disrupt RGS14’s effects on plasticity. This review will focus on the known and unexplored roles of RGS14 in cell signaling, physiology, disease and behavior.
Highlights
single nucleotide polymorphisms (SNPs) within the regulator of G-protein signaling 14 (RGS14) gene are associated with elevated levels of parathyroid hormone (PTH) [41] and fibroblast growth factor 23 (FGF23) [42], which are both critical for proper kidney function [43]
An additional population of presumably excitatory RGS14-containing inputs of yet-unknown origin is found in the substantia nigra pars reticulata. Another region enriched with RGS14 is the amygdala, in which expression is found in putative projection neurons of the basomedial, basolateral, and centrolateral nuclei [19,56]
As cocaine-induced locomotion is partially dependent on various Gi/o-coupled receptors [96,97], RGS14 may limit postsynaptic signaling caused by increased monoamine stimulation in either medium spiny neurons (MSNs) or elsewhere to modulate locomotor responses to cocaine
Summary
The family of the regulators of G-protein signaling (RGS) proteins regulate G-proteincoupled receptors (GPCRs) and G-protein signaling events [1,2]. Gα subunits have intrinsic GTPase activity, which allows them to hydrolyze their bound GTP to GDP and terminate G-protein signaling. RGS proteins bind directly to GPCRs and G proteins [1] to act as GTPase-activating proteins (GAPs) and markedly accelerate the hydrolysis of Gα-bound GTP to GDP, and the consequent deactivation of G-protein signaling [5,6]. RGS14 structural structural organization organization and kDa protein that contains three conserved domains and two motifs. The domain serves as a GTPase activating protein that contains three conserved domains and two motifs. The RGS domain serves as a GTPase activating proteinprotein (GAP). RGS14 contains a nuclear localization sequence (NLS) in the linker region dissociation. RGS14 contains a nuclear localization sequencewithin (NLS) in linker region between between the of andfrom. Motif (DSAL) is found at the C-terminus of human/primate (but not rodent) RGS14, which mediates RGS14 interactions with NHERF1
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