Small G protein signaling in neuronal plasticity and memory formation: the specific role of ras family proteins

Abstract

Small G proteins are an extensive family of proteins that bind and hydrolyze GTP. They are ubiquitous inside cells, regulating a wide range of cellular processes. Recently, many studies have examined the role of small G proteins, particularly the Ras family of G proteins, in memory formation. Once thought to be primarily involved in the transduction of a variety of extracellular signals during development, it is now clear that Ras family proteins also play critical roles in molecular processing underlying neuronal and behavioral plasticity. We here review a number of recent studies that explore how the signaling of Ras family proteins contributes to memory formation. Understanding these signaling processes is of fundamental importance both from a basic scientific perspective, with the goal of providing mechanistic insights into a critical aspect of cognitive behavior, and from a clinical perspective, with the goal of providing effective therapies for a range of disorders involving cognitive impairments.

Figure 1. Biochemical properties of the signaling of Ras family proteins

A. The cycling of Ras family proteins between inactive and active states. B. The signaling properties of specific inhibitors (GAP) and activators (GEF) of Ras family proteins (SEC14: Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein, lipid-binding; PH: Pleckstrin homology domain, lipid-binding; C2: membrane targeting and Ca ²⁺-binding; SH3-B: Src Homology 3-binding motif; QTRV: C-terminal amino acids binding to PSD-95; ActB: actin binding domain; PDZ: anchor transmembrane proteins to the cytoskeleton; GKBD: guanylate kinase binding domain; IQ: Ca ²⁺/CaM binding domain; REM: Ras-Exchanger-motif domain, stabilizing Ras activation; DEP: Dishevelled-Egl10-Pleckstrin domain, important for membrane localization; CNB: cAMP-binding domain; RA: Ras-association domain; Rac: a member of the Rho family of small G-proteins).

Figure 2. Major downstream signaling cascades of Ras family proteins

Solid green arrows indicate direct activation; dashed green arrows indicate indirect activation via intermediate steps that have yet to be specified; red projections indicate inhibition.

Figure 3. Regulation of different aspects of synaptic plasticity by GAPs and GEFs during memory formation

A. Neurofibromin (NF1) regulates the release of inhibitory neurotransmitter, GABA, which binds to GABA receptors on dendritic shafts. B. SynGAP localizes in dendritic spines and regulates AMPAR-mediated LTP and LTD. C. RasGRFs also localize in dendritic spines and regulates AMPAR dynamics. In addition, there is also evidence that RasGRF1 can regulate excitability and RasGRFs can regulate short-term presynaptic facilitation (see text); however, the underlying molecular mechanism is not clear. D. Epac can regulate both glutamate release in presynaptic terminals and AMPAR dynamics in post-synaptic spines.

Figure 4. The dynamics of Ras family proteins during memory formation and neuronal plasticity

A. The circadian oscillation of hippocampal Ras-ERK activity restricts the temporal window for the induction and expression of long-term memory. Area shaded in green and red indicates permissive and non-permissive window, respectively, for the induction and expression of long-term memory. B. Ras activated by a strong glutamate uncaging stimuli at a single spine can spread to and invade neighboring spines and allow the induction of sustained spine enlargement by sub-threshold stimuli. Distal spines which do not receive the activated Ras fail to express LTP. C. The interaction between Ras and Rap1 activity controls ERK activation induced by different patterns of training, and differentially route the activated ERK to distinct downstream signaling elements, giving rise to different forms of synaptic facilitation.