Co-expression of metabotropic glutamate receptor type 1α with Homer-1a/Vesl-1S increases the cell surface expression of the receptor

Ciruela, Francisco; Soloviev, Mikhail; McIlhinney, R. A. Jeffrey

doi:10.1042/0264-6021:3410795

Cited by 70 publications

(77 citation statements)

References 24 publications

(48 reference statements)

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“…The error bar shows S.E. cell surface expression of group I metabotropic glutamate receptors 1/5 and promote remodeling of synapses, considering the recent observations that the cell surface expression of group I metabotropic glutamate receptors 1/5 were increased when co-expressed with Vesl-1S and that this increase was inhibited by Vesl-1L (34,35).…”

Section: Vesl-1s/homer-1a Regulation By Proteasomesmentioning

confidence: 99%

Regulation of the Level of Vesl-1S/Homer-1a Proteins by Ubiquitin-Proteasome Proteolytic Systems

Ageta

Kato

Hatakeyama

et al. 2001

Journal of Biological Chemistry

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The vesl-1S/homer-1a gene is up-regulated during seizure and long term potentiation. Other members of the Vesl family, Vesl-1L, -2, and -3, are constitutively expressed in the brain. We examined the regulatory mechanisms governing the expression level of Vesl-1S protein, either an exogenously introduced one in COS7 or human embryonic kidney 293T cells or an endogenous one in rat brain neurons in cultures. In both cases, application of proteasome inhibitors increased the amount of Vesl-1S protein but not that of Vesl-1L, -2, or -3 protein. Deletion analyses revealed that the C-terminal 11-amino acid region was responsible for the proteolysis of Vesl-1S by proteasomes. Application of proteasome inhibitors promoted ubiquitination of Vesl-1S protein but not that of the Vesl-1S deletion mutant, which evaded proteasome-mediated degradation. These results indicate that ubiquitin-proteasome systems are involved in the regulation of the expression level of Vesl-1S protein. Long term potentiation (LTP),1 which is thought to underlie mechanisms of learning and memory, has two distinct phases. The early-phase LTP lasts for no more than several hours and does not depend on protein synthesis, whereas the late-phase LTP (L-LTP) lasts for weeks in vivo and depends on de novo RNA transcription and protein synthesis (1-3). The formation of long term memory requires de novo RNA transcription and protein synthesis (4 -6). Thus, activity-dependent gene expression is expected to play a critical role in long term memory.Vesl-1S/Homer-1a was isolated as a gene whose expression was up-regulated following LTP induction (7,8). Vesl-1L/Homer-1c/PSD-Zip45 and Vesl-1L(⌬12)/Homer-1b, which are splice variants of Vesl-1S, are constitutively expressed in the brain. Vesl-2/Homer-2b, Vesl-2(⌬11)/Homer-2a, and Vesl-3/Homer-3 are highly related to Vesl-1L in that both contain EVH1 domains in their N termini and leucine zippers in their C termini that mediate multimerization (9 -11). The EVH1 domains of Vesl family proteins interact with group I metabotropic glutamate receptors 1/5 (7) and inositol trisphosphate receptors (12). Moreover, Vesl family proteins interact with the Shank protein, which binds to the NMDAR⅐PSD-95⅐GKAP complex and cortactin (13,14). Thus Vesl family proteins may be a component of huge PSD-95 protein complexes located in postsynaptic regions.The level of vesl-1S mRNA in the hippocampus is drastically increased during seizure and LTP, but the increase in the amount of Vesl-1S protein is limited (9). Moreover, all members of Vesl family contain PEST sequences that are thought to be ubiquitin-proteasome-dependent degradation signals (15). We considered that the amount of Vesl-1S protein might be regulated by certain proteases. The ubiquitin-proteasome pathway, one of the protein degradation systems of the cell, is involved in a variety of cellular processes, for instance, cell cycling (16), transcriptional activation (17), apoptosis (18), circadian rhythm (19), neurodegeneration (20), and neuronal plasticity (21,22). Protein ubi...

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Section: Vesl-1s/homer-1a Regulation By Proteasomesmentioning

confidence: 99%

Regulation of the Level of Vesl-1S/Homer-1a Proteins by Ubiquitin-Proteasome Proteolytic Systems

Ageta

Kato

Hatakeyama

et al. 2001

Journal of Biological Chemistry

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“…Homer-1b predominantly localizes to the rat hippocampus. Binding of homer-1b with mGluR1␣ and mGluR5␣ receptors may lead to stabilization and cell-surface targeting of the receptors in their signaling pathways (51). Homer-1b is a novel protein that has been described in the protein data base since 1999 (ca.expasy.org).…”

Section: Effect Of Eh and Sh On Renal Kallikreinmentioning

confidence: 99%

Proteomic Analysis Reveals Alterations in the Renal Kallikrein Pathway during Hypoxia-Induced Hypertension

Thongboonkerd¹,

Gozal

Sachleben

et al. 2002

Journal of Biological Chemistry

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Obstructive sleep apnea syndrome (OSAS), a disorder characterized by episodic hypoxia (EH) during sleep, is associated with systemic hypertension. We used proteomic analysis to examine differences in rat kidney protein expression during EH, and their potential relationship to EH-induced hypertension. Young male Sprague-Dawley rats were exposed to either EH or sustained hypoxia (SH) for 14 (EH14/SH14) and 30 (EH30/SH30) days. Mean arterial blood pressure was significantly increased only in EH30 (p < 0.0002). Kidney proteins were resolved by two-dimensional-PAGE and were identified by MALDI-MS. Renal expression of kallistatin, a potent vasodilator, was down-regulated in all animals. Expression of ␣-1-antitrypsin, an inhibitor of kallikrein activation, was up-regulated in EH but down-regulated in SH. Western blotting showed significant elevation of B 2 -bradykinin receptor expression in all normotensive animals but remained unchanged in hypertensive animals. Proteins relevant to vascular hypertrophy, such as smooth muscle myosin and protein-disulfide isomerase were up-regulated in EH30 but were down-regulated in SH30. These data indicate that EH induces changes in renal protein expression consistent with impairment of vasodilation mediated by the kallikrein-kallistatin pathway and vascular hypertrophy. In contrast, SH-induced changes suggest the kallikrein-and bradykinin-mediated compensatory mechanisms for prevention of hypertension and vascular remodeling. To test the hypothesis suggested by the proteomic data, we measured the effect of EH on blood pressure in transgenic hKLK1 rats that overexpress human kallikrein. Transgenic hKLK1 animals were protected from EH-induced hypertension. We conclude that EH-induced hypertension may result, at least in part, from altered regulation of the renal kallikrein system.Obstructive sleep apnea syndrome (OSAS), 1 a disorder characterized by episodic hypoxia (EH), is a major public health problem (1-3). OSAS affects 4 -5% of the general adult population in United States and 1-2% of children (4 -6). One of the major consequences of untreated OSAS is systemic hypertension (7, 8), with a prevalence ranging from 15 to 56% (8 -10). Indeed, OSAS has been demonstrated to be an independent risk factor for systemic hypertension, and the relative risk is elevated even in young children (8, 11). Moreover, OSAS has also been associated with both proteinuria and end-stage renal disease (12).The pathophysiology of systemic hypertension in OSAS is complex. Increased sympathetic nervous system activity induced by the intermittent hypoxia that characteristically accompanies OSAS appears to mediate hypertension during OSAS via a mechanism that requires changes in the vasoreactivity of resistance vascular beds such as the kidney (13-19). Indeed, sustained hypoxia (SH) does not lead to hypertension as do pharmacologically-mediated decreases of angiotensin II levels and blockade of angiotensin receptors (20,21). These data suggest that changes in renal vasoconstrictors play a major role in the dev...

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“…Binding to Homers can alter the function of TRPC1 (12), and group I mGluRs couple more strongly to some effectors (e.g., ion channels) when bound to Homer 1a (13) and more strongly to others, such as IP 3 Rs (8), when bound to long Homer proteins. Thus, Homer proteins regulate localization of binding partners (13)(14)(15)(16)(17)(18) and assemble groups of molecules into putative signaling microdomains (8,13). However, no study to date has demonstrated the functional consequences of Homer expression on receptor-effector coupling for mGluRs located at the postsynaptic site in mammalian neurons.…”

mentioning

confidence: 99%

Homer 1a uncouples metabotropic glutamate receptor 5 from postsynaptic effectors

Kammermeier

Worley²

2007

Proc. Natl. Acad. Sci. U.S.A.

114

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Metabotropic glutamate receptors (mGluRs) and Homer proteins play critical roles in neuronal functions including plasticity, nociception, epilepsy, and drug addiction. Furthermore, Homer proteins regulate mGluR1/5 function by acting as adapters and facilitating coupling to effectors such as the inositol triphosphate receptor. However, although Homer proteins and their interaction with mGluRs have been the subject of intense study, direct measurements of Homer-induced changes in postsynaptic mGluReffector coupling have not been reported. This question was addressed here by examining glutamatergic excitatory postsynaptic currents (EPSCs) in rat autaptic hippocampal cultures. In most neurons, the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine strongly inhibited the EPSC acutely. This modulation occurred postsynaptically, was mediated primarily by mGluR5, and was inositol triphosphate receptor-dependent. Expression of the dominant negative, immediate early form of Homer, Homer 1a, strongly reduced EPSC modulation, but the W24A mutant of Homer 1a, which cannot bind mGluRs, had no effect. (S)-3,5-dihydroxyphenylglycine-mediated intracellular calcium responses in the processes of Homer 1a-expressing neurons were reduced compared with those in Homer 1a W24A-expressing cells. However, neither the distribution of mGluR5 nor the modulation of somatic calcium channels was altered by Homer 1a expression. These data demonstrate that Homer 1a can reduce mGluR5 coupling to postsynaptic effectors without relying on large changes in the subcellular distribution of the receptor. Thus, alteration of mGluR signaling by changes in Homer protein expression may represent a viable mechanism for fine-tuning synaptic strength in neurons.autapse ͉ calcium channel ͉ excitatory postsynaptic current ͉ hippocampal M etabotropic glutamate receptors (mGluRs) are class 3 G protein-coupled receptors expressed throughout the brain. Group I mGluRs 1 and 5 couple to the phospholipase C/calcium release cascade and to pathways regulating ion channels and synaptic currents (1, 2). In the brain, group I mGluRs are often expressed postsynaptically, where they regulate NMDA and AMPA receptor function and mediate multiple forms of plasticity (3).The Homer family of postsynaptic scaffolding proteins was discovered by the regulated expression of the member subsequently termed Homer 1a (4). Levels of Homer 1a and variant Ania-3 are increased after periods of activity or stress, injury, or novel experience (4, 5). Other ''long'' Homer proteins (1b, 1c, 2, and 3) are expressed constitutively (6-8) and, unlike Homer 1a, form clusters mediated by their long C termini. Homer proteins organize postsynaptic proteins around the active site (7) by binding several targets including group I mGluRs, inositol triphosphate receptors (IP 3 Rs), Shank, and the TRPC1 cation channel (9-12).Homer proteins also influence the function of their binding partners. Binding to Homers can alter the function of TRPC1 (12), and group I mGluRs couple more strongly to some effectors (...

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Co-expression of metabotropic glutamate receptor type 1α with Homer-1a/Vesl-1S increases the cell surface expression of the receptor

Cited by 70 publications

References 24 publications

Regulation of the Level of Vesl-1S/Homer-1a Proteins by Ubiquitin-Proteasome Proteolytic Systems

Regulation of the Level of Vesl-1S/Homer-1a Proteins by Ubiquitin-Proteasome Proteolytic Systems

Proteomic Analysis Reveals Alterations in the Renal Kallikrein Pathway during Hypoxia-Induced Hypertension

Homer 1a uncouples metabotropic glutamate receptor 5 from postsynaptic effectors

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