Rap1-induced p38 Mitogen-activated Protein Kinase Activation Facilitates AMPA Receptor Trafficking via the GDI·Rab5 Complex

Abstract

Recent evidence has emphasized the importance of p38 mitogen-activated protein kinase (MAPK) in the induction of metabotropic glutamate receptor (mGluR)-dependent long term depression (LTD) at hippocampal CA3-CA1 synapses. However, the cascade responsible of mGluR to activate p38 MAPK and the signaling pathway immediately downstream from it to induce synaptic depression is poorly understood. Here, we show that transient activation of group I mGluR with the selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) activates p38 MAPK through G protein ␤␥-subunit, small GTPase Rap1, and MAPK kinase 3/6 (MKK3/6), thus resulting in mGluR5-dependent LTD. Furthermore, our data clearly show that an accelerating AMPA receptor endocytosis by stimulating the formation of guanyl nucleotide dissociation inhibitor-Rab5 complex is a potential downstream processing of p38 MAPK activation to mediate DHPG-LTD. These results suggest an important role for Rap1-MKK3/6-p38 MAPK pathway in the induction of mGluR-dependent LTD by directly coupling to receptor trafficking machineries to facilitate the loss of synaptic AMPA receptors.Long term depression (LTD) 1 is a persistent activity-dependent decrease of synaptic efficacy that together with the converse process, long term potentiation, has been considered to be crucial for information storage in the brain (1, 2). In the hippocampus, LTD is divided into three categories: homosynaptic, heterosynaptic, and associative LTD (3). The bestcharacterized form of homosynaptic LTD is induced in the CA1 region of the hippocampus by prolonged low frequency synaptic stimulation via a NMDA receptor-dependent rise in postsynaptic [Ca 2ϩ ] i and the activation of serine/threonine protein phosphatases (4). Recent work has shown that mechanistically distinct type of LTD can be induced in the CA1 region by other types of synaptic stimulation or brief pharmacological treatments. For example, a prolonged period of paired-pulse stimulation or a direct application of the selective group I mGluR agonists, such as DHPG, can induce a robust mGluR-dependent form of LTD that is independent of NMDA receptor activation (5). In contrast to the mechanisms of NMDA receptor-dependent LTD, which are fairly well established, the mechanisms of induction and the site of expression of mGluR-dependent LTD are still a matter of some considerable debate. Current studies have reported that the induction of mGluR-dependent LTD does not require extracellular Ca 2ϩ (6), Ca 2ϩ release from intracellular stores (7), activation of Ca 2ϩ /calmodulin-dependent protein kinase II (8), protein kinase A or protein kinase C (7, 9), or serine/ threonine protein phosphatases (9). However, this form of LTD requires activation of G q -type G proteins (10), a local translation of dendritic mRNA (5, 11), a long-lasting loss of postsynaptic AMPA receptors (12, 13), and activation of protein tyrosine phosphatases (14). In addition, more recent studies suggest that p38 MAPK signaling also serves as a signal mediator in the induction of mGluR-depende...

p38MAPK Signaling and Desmoglein-3 Internalization Are Linked Events in Pemphigus Acantholysis

“…The demonstration that p38MAPK may play an important role in receptor endocytosis is not new. Several articles have shown that p38MAPK regulates Rab5 proteins and its effectors (21)(22)(23). Rab5 proteins are essential in regulating the endocytosis of numerous receptors.…”

Loss of Metabotropic Glutamate Receptor-Dependent Long-Term Depression via Downregulation of mGluR5 after Status Epilepticus

“…Available evidence suggests that of the two group I mGluRs, mGluR5 is responsible for mediating LTD induced by application of DHPG Faas et al, 2002;Huang et al, 2004) (but see Volk et al, 2006) as well as by PP LFS (Faas et al, 2002). In addition to the anatomical localization of mGluR5 at postsynaptic sites, the importance of postsynaptic mechanisms in the induction and expression of mGluR LTD is supported by experiments using postsynaptic injection of G-protein inhibitors (Watabe et al, 2002;Huang et al, 2004), or endocytosis and protein synthesis inhibitors that prevent glutamate receptor internalization (Snyder et al, 2001;Xiao et al, 2001), as well as experiments assessing changes in presynaptic release directly (Zhang et al, 2006). Intriguingly, these mechanisms may be different in neonatal hippocampus, with mGluR LTD relying on large presynaptic changes (Nosyreva and Huber, 2005).…”

Rab11A Controls the Biogenesis of Birbeck Granules by Regulating Langerin Recycling and Stability

“…The siRNA sequence against Rab4A (sense 5Ј-GCCAGAACAUUGUGAUCAUd(TT)-3Ј) was kindly provided by M. Cormont (Faculté de Médecine de Nice, Nice, France). The siRNAs against Rab6A/AЈ (Del Nery et al, 2006) and against Rab5A were published previously (Huang et al, 2004), whereas the siRNAs against RCP and Rip11 were described by Peden et al (2004). Cells were transfected with the siRNAs, by using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions.…”