Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

Abstract

The regulator of G protein signaling (RGS) family of proteins serves critical roles in G protein-coupled receptor (GPCR) and heterotrimeric G protein signal transduction. RGS proteins are best understood as negative regulators of GPCR/G protein signaling. They achieve this by acting as GTPase activating proteins (GAPs) for Ga subunits and accelerating the turnoff of G protein signaling. Many RGS proteins also bind additional signaling partners that either regulate their functions or enable them to regulate other important signaling events. At neuronal synapses, GPCRs, G proteins, and RGS proteins work in coordination to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity, which are necessary for central nervous system physiology and behavior. Accumulating evidence has revealed key roles for specific RGS proteins in multiple signaling pathways at neuronal synapses, regulating both pre-and postsynaptic signaling events and synaptic plasticity. Here, we review and highlight the current knowledge of specific RGS proteins (RGS2, RGS4, RGS7, RGS9-2, and RGS14) that have been clearly demonstrated to serve critical roles in modulating synaptic signaling and plasticity throughout the brain, and we consider their potential as future therapeutic targets.

Scale Invariant Disordered Nanotopography Promotes Hippocampal Neuron Development and Maturation with Involvement of Mechanotransductive Pathways

“…Calmodulin itself is upregulated, in line with its essential function in calcium signaling-regulated synaptic plasticity (Wayman et al, 2008). In addition, Gαq is upregulated, a heterotrimeric G protein which regulates synaptic signaling by mediating the downstream effects of many neurotransmitters and hormones (Gerber et al, 2016). Also two members of the calpain family are downregulated (Capn2, calpain-2; Capns1, calpain 4).…”

The impact of RGS and other G-protein regulatory proteins on Gαi-mediated signaling in immunity

“…Rgs2 is highly expressed in neutrophils, while Rgs1 is not, and in contrast to Rgs1 , Rgs2 expression is not interferon inducible (16). Despite the similar expression pattern to Rgs1 , Rgs2 has not been linked to diseases of the immune system, but rather to cardiovascular and central nervous system dysfunction (91,92). However, analysis of mice lacking Rgs2 expression did reveal a role for RGS2 in T cell proliferation and anti-viral immune responses (93).…”

“…In the brain Rgs14 is expressed in neurons in the hippocampus and olfactory cortex, where it suppresses synaptic plasticity. Mice lacking Rgs14 perform better than do wild-type mice in hippocampus-dependent tasks (91). The impact of the loss of Rgs14 on the adaptive or innate immune system has not been reported.…”

Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases

“…GPCRs regulate signaling pathways involved in a diverse range of events including pain, mood, appetite, vision, the immune system, and cognition. By modulating neurotransmitter release and binding they also play a role in slow synaptic transmission [70,71]. GPCRs are targeted by approximately 30% of FDA-approved drugs [72] and are among the most successful therapeutic targets for diseases including diabetes [73], inflammatory diseases [74], neurodegeneration [75], cardiovascular disease [76], and some psychiatric disorders [77].…”