RGS14 at the interface of hippocampal signaling and synaptic plasticity

Abstract

Learning and memory are encoded within the brain as biochemical and physical changes at synapses that alter synaptic transmission, a process known as synaptic plasticity. Although much is known about factors that positively regulate synaptic plasticity, very little is known about factors that negatively regulate this process. Recently, the signaling protein RGS14 (Regulator of G protein Signaling 14) was identified as a natural suppressor of hippocampal-based learning and memory as well as synaptic plasticity within CA2 hippocampal neurons. RGS14 is a multifunctional scaffolding protein that integrates unconventional G protein and mitogen-activated protein (MAP) kinase signaling pathways that are themselves key regulators of synaptic plasticity, learning, and memory. Here, we highlight the known roles for RGS14 in brain physiology and unconventional G protein signaling pathways, and propose molecular models to describe how RGS14 may integrate these diverse signaling pathways to modulate synaptic plasticity in CA2 hippocampal neurons.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1. RGS14 domain structure and its identified binding partners

Top: RGS14 directly binds activated Gαi family members and Gαo through its RGS domain, and it also specifically binds inactive Gαi1 and Gαi3 via its GPR domain. Activated H-Ras, Rap2, and Raf kinases directly interact with the Ras/Rap-binding domains (R1 and R2). Bottom: RGS14 is structurally and functionally unique in that it shares both an RGS domain and a GPR domain that places it and its closest relative RGS12 into both the RGS protein and the Group II AGS protein (GPR domain-containing) subfamilies.

Figure 2. Hippocampal circuitry and possible roles for RGS14 in the suppression of LTP in CA2 neurons

(A) Diagram of hippocampal circuitry. Red arrows indicate the classical dentate gyrus (DG)-CA3-CA1 trisynaptic circuit. Input from the entorhinal cortex (EC) synapse on granule neurons in the DG. Mossy fiber projections from DG synapse on CA3 pyramidal neurons. Schaffer Collateral (SC) projections from CA3 (red pathway) synapse on CA1 neurons to complete the trisynaptic circuit. The blue arrow indicates CA3 Schaffer collaterals distinct from the trisynaptic circuit that synapse on CA2 pyramidal neurons. Green arrows indicate separate circuits in which distinct EC inputs (LII and LIII) synapse on CA2 dendrites. These CA2 neurons subsequently project to CA1. (B) Differential synaptic plasticity on CA2 pyramidal neurons is elicited by distinct synaptic inputs. Layers of the hippocampus are shown at left; Stratum Oriens (so), Pyramidal Cell Layer (pcl), Stratum Radiatum (sr), and Stratum-lacunosum moleculare (sl-m). CA3 Schaffer collateral (blue) synapse on proximal apical dendrites of CA2 neurons within the Stratum Radiatum. High frequency stimulation of Schaffer collaterals generates no LTP in CA2 proximal dendrites. Projections from layer II and III of the EC (green) synapse on distal apical dendrites within the sl-m layer. Stimulation of EC inputs generates LTP in CA2 distal dendrites. (C) Cartoon model of a dendritic spine from CA2 neurons that express RGS14, and potential roles for RGS14 in the negative regulation of CA2 synaptic plasticity. Shown are distinct properties and signaling proteins that are uniquely or highly expressed in CA2 neurons (blue), additional signaling proteins that are involved in synaptic plasticity (gray), and proposed roles for RGS14 (red).

Figure 3. Conventional vs. unconventional G protein signaling

Top: Before stimulation, conventional GPCR/G protein signaling (left) consists of a GPCR, Gαi-GDP bound to Gβγ, and a downstream effector protein (i.e. Adenylyl cyclase; ACyc). In unconventional signaling (right), a cytosolic GEF substitutes for and serves a role similar to that of the GPCR, while the GPR protein, perhaps in complex with an effector, substitutes for Gβγ. Bottom: In the presence of a stimulating neurotransmitter or hormone (NT/H), the GPCR exhibits GEF activity towards Gαi, resulting in GTP binding, heterotrimer dissociation, and subsequent Gαi-GTP and Gβγ coupling to the effector protein to regulate signaling pathways. In unconventional signaling, the cytosolic GEF catalyzes GTP exchange on the Gαi subunit, resulting in free Gαi-GTP, GPR protein, and effector that are able to regulate downstream signaling.

Figure 4. Proposed working model for how the RGS, RBD, and GPR domains of RGS14 may function coordinately to regulate Gαi signaling

The proposed model for RGS14 signaling proceeds clockwise from top left. (1) RGS14 pre-exists in complex with inactive Gαi-GDP via its GPR motif at the plasma membrane in its basal resting state. (2) An unknown stimulation event, perhaps through a receptor tyrosine kinase to stimulate Ras and/or neurotransmitter (NT) activation of a GPCR, induces recruitment of a GEF to the RGS14:Gαi-GDP complex. (3) After binding the RGS14:Gαi-GDP complex, the GEF catalyzes nucleotide exchange on and GTP binding to the Gαi, thereby releasing RGS14 which is now free to bind activated Ras/Raf via its RBDs. (4) Active Gαi-GTP dissociates from RGS14, allowing it to serve as a scaffold to assemble Ras and Raf in a signaling complex. (5) In some regulated fashion, the adjacent RGS domain recognizes the active Gαi to accelerate Gα-GTP hydrolysis, resulting in signal termination. The nearby GPR domain re-binds Gαi-GDP and causes Raf and Ras to dissociate, leading to reformation of the inactive RGS14:Gαi-GDP complex and a return to the basal resting state (1).