Sônia A. L. Corrêa

The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease

A significant amount of evidence suggests that the p38-mitogen-activated protein kinase (MAPK) signalling cascade plays a crucial role in synaptic plasticity and in neurodegenerative diseases. In this review we will discuss the cellular localisation and activation of p38 MAPK and the recent advances on the molecular and cellular mechanisms of its substrates: MAPKAPK 2 (MK2) and tau protein. In particular we will focus our attention on the understanding of the p38 MAPK-MK2 and p38 MAPK-tau activation axis in controlling neuroinflammation, actin remodelling and tau hyperphosphorylation, processes that are thought to be involved in normal ageing as well as in neurodegenerative diseases. We will also give some insight into how elucidating the precise role of p38 MAPK-MK2 and p38 MAPK-tau signalling cascades may help to identify novel therapeutic targets to slow down the symptoms observed in neurodegenerative diseases such as Alzheimers and Parkinsons disease.

Co‐activation of p38 mitogen‐activated protein kinase and protein tyrosine phosphatase underlies metabotropic glutamate receptor‐dependent long‐term depression

Long‐term potentiation (LTP) and long‐term depression (LTD) are forms of synaptic plasticity thought to contribute to learning and memory. Much is known about the mechanisms of NMDA receptor‐dependent LTD in the CA1 region of rat hippocampus but there is still considerable uncertainty about the mechanisms of LTD induced by mGluR activation (mGluR‐LTD). Furthermore, data on mGluR‐LTD derives largely from studies using pharmacologically induced LTD. To investigate mGluR‐LTD that is more physiologically relevant we have examined, in CA1 of adult rat hippocampus, mechanisms of synaptically induced mGluR‐LTD. We provide the first demonstration that activation of protein tyrosine phosphatase (PTP) is essential for the induction of synaptically induced mGluR‐LTD. In addition, we show that activation of p38 MAPK is also required for this form of LTD. Furthermore, LTD can be mimicked and occluded by activation of p38 MAPK, provided that protein tyrosine kinases (PTKs) are inhibited. These data therefore demonstrate that a novel combination of signalling cascades, requiring both activation of p38 MAPK and tyrosine de‐phosphorylation, underlies the induction of synaptically induced mGluR‐LTD.

Triad3A Regulates Synaptic Strength by Ubiquitination of Arc

Activity-dependent gene transcription and protein synthesis underlie many forms of learning-related synaptic plasticity. At excitatory glutamatergic synapses, the immediate early gene product Arc/Arg3.1 couples synaptic activity to postsynaptic endocytosis of AMPA-type glutamate receptors. Although the mechanisms for Arc induction have been described, little is known regarding the molecular machinery that terminates Arc function. Here, we demonstrate that the RING domain ubiquitin ligase Triad3A/RNF216 ubiquitinates Arc, resulting in its rapid proteasomal degradation. Triad3A associates with Arc, localizes to clathrin-coated pits, and is associated with endocytic sites in dendrites and spines. In the absence of Triad3A, Arc accumulates, leading to the loss of surface AMPA receptors. Furthermore, loss of Triad3A mimics and occludes Arc-dependent forms of synaptic plasticity. Thus, degradation of Arc by clathrin-localized Triad3A regulates the availability of synaptic AMPA receptors and temporally tunes Arc-mediated plasticity at glutamatergic synapses.

MSK1 Regulates Homeostatic and Experience-Dependent Synaptic Plasticity

The ability of neurons to modulate synaptic strength underpins synaptic plasticity, learning and memory, and adaptation to sensory experience. Despite the importance of synaptic adaptation in directing, reinforcing, and revising the behavioral response to environmental influences, the cellular and molecular mechanisms underlying synaptic adaptation are far from clear. Brain-derived neurotrophic factor (BDNF) is a prime initiator of structural and functional synaptic adaptation. However, the signaling cascade activated by BDNF to initiate these adaptive changes has not been elucidated. We have previously shown that BDNF activates mitogen- and stress-activated kinase 1 (MSK1), which regulates gene transcription via the phosphorylation of both CREB and histone H3. Using mice with a kinase-dead knock-in mutation of MSK1, we now show that MSK1 is necessary for the upregulation of synaptic strength in response to environmental enrichment in vivo. Furthermore, neurons from MSK1 kinase-dead mice failed to show scaling of synaptic transmission in response to activity deprivation in vitro, a deficit that could be rescued by reintroduction of wild-type MSK1. We also show that MSK1 forms part of a BDNF- and MAPK-dependent signaling cascade required for homeostatic synaptic scaling, which likely resides in the ability of MSK1 to regulate cell surface GluA1 expression via the induction of Arc/Arg3.1. These results demonstrate that MSK1 is an integral part of a signaling pathway that underlies the adaptive response to synaptic and environmental experience. MSK1 may thus act as a key homeostat in the activity- and experience-dependent regulation of synaptic strength.

Negative feedback regulation of the ERK1/2 MAPK pathway

The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway regulates many cellular functions, including proliferation, differentiation, and transformation. To reliably convert external stimuli into specific cellular responses and to adapt to environmental circumstances, the pathway must be integrated into the overall signalling activity of the cell. Multiple mechanisms have evolved to perform this role. In this review, we will focus on negative feedback mechanisms and examine how they shape ERK1/2 MAPK signalling. We will first discuss the extensive number of negative feedback loops targeting the different components of the ERK1/2 MAPK cascade, specifically the direct posttranslational modification of pathway components by downstream protein kinases and the induction of de novo gene synthesis of specific pathway inhibitors. We will then evaluate how negative feedback modulates the spatiotemporal signalling dynamics of the ERK1/2 pathway regarding signalling amplitude and duration as well as subcellular localisation. Aberrant ERK1/2 activation results in deregulated proliferation and malignant transformation in model systems and is commonly observed in human tumours. Inhibition of the ERK1/2 pathway thus represents an attractive target for the treatment of malignant tumours with increased ERK1/2 activity. We will, therefore, discuss the effect of ERK1/2 MAPK feedback regulation on cancer treatment and how it contributes to reduced clinical efficacy of therapeutic agents and the development of drug resistance.

GISP: a novel brain-specific protein that promotes surface expression and function of GABAB receptors

Synaptic transmission depends on the regulated surface expression of neurotransmitter receptors, but many of the cellular processes required to achieve this remain poorly understood. To better define specific mechanisms for the GABAB receptor (GABABR) trafficking, we screened for proteins that bind to the carboxy‐terminus of the GABAB1 subunit. We report the identification and characterization of a novel 130‐kDa protein, GPCR interacting scaffolding protein (GISP), that interacts directly with the GABAB1 subunit via a coiled‐coil domain. GISP co‐fractionates with GABABR and with the postsynaptic density and co‐immunoprecipitates with GABAB1 and GABAB2 from rat brain. In cultured hippocampal neurons, GISP displays a punctate dendritic distribution and has an overlapping localization with GABABRs. When co‐expressed with GABABRs in human embryonic kidney cells, GISP promotes GABABR surface expression and enhances both baclofen‐evoked extracellular signal‐regulated kinase (ERK) phosphorylation and G‐protein inwardly rectifying potassium channel (GIRK) currents. These results suggest that GISP is involved in the forward trafficking and stabilization of functional GABABRs.

Disruption of the interaction between myosin VI and SAP97 is associated with a reduction in the number of AMPARs at hippocampal synapses

J. Neurochem. (2010) 112, 677–690.

GISP binding to TSG101 increases GABAB receptor stability by down-regulating ESCRT-mediated lysosomal degradation

The neuron‐specific G protein‐coupled receptor interacting scaffold protein (GISP) is a multidomain, brain‐specific protein derived from the A‐kinase anchoring protein‐9 gene. We originally isolated GISP as an interacting partner for the GABAB receptor subunit GABAB1. Here, we show that the protein tumour susceptibility gene 101 (TSG101), an integral component of the endosomal sorting machinery that targets membrane proteins for lysosomal degradation, also interacts with GISP. TSG101 co‐immunoprecipitates with GISP from adult rat brain, and using GST pull‐downs, we identified that the eighth coiled‐coiled region of GISP is critical for TSG101 association. Intriguingly, although there is no direct interaction between GISP and the GABAB2 subunit, their co‐expression in HEK293 cells increases levels of GABAB2. GISP also inhibits TSG101‐dependent GABAB2 down‐regulation in human embryonic kidney 293 cells whereas over‐expression of a mutant GISP lacking the TSG101 binding domain has no effect on GABAB2 degradation. These data suggest that GISP can function as a negative regulator of TSG101‐dependent lysosomal degradation of transmembrane proteins in neurons to promote receptor stability.

LTP in hippocampal neurons is associated with a CaMKII-mediated increase in GluA1 surface expression.

J. Neurochem. (2011) 116, 530–543.

Hippocampal metabotropic glutamate receptor long-term depression in health and disease: focus on mitogen-activated protein kinase pathways.

Group I metabotropic glutamate receptor (mGluR) dependent long‐term depression (LTD) is a major form of synaptic plasticity underlying learning and memory. The molecular mechanisms involved in mGluR‐LTD have been investigated intensively for the last two decades. In this 60th anniversary special issue article, we review the recent advances in determining the mechanisms that regulate the induction, transduction and expression of mGluR‐LTD in the hippocampus, with a focus on the mitogen‐activated protein kinase (MAPK) pathways. In particular we discuss the requirement of p38 MAPK and extracellular signal‐regulated kinase 1/2 (ERK 1/2) activation. The recent advances in understanding the signaling cascades regulating mGluR‐LTD are then related to the cognitive impairments observed in neurological disorders, such as fragile X syndrome and Alzheimers disease.