PKC phosphorylation of a conserved serine residue in the C‐terminus of group III metabotropic glutamate receptors inhibits calmodulin binding

Airas, José M.; Betz, Heinrich; Far, Oussama El

doi:10.1016/s0014-5793(01)02311-0

Cited by 48 publications

(62 citation statements)

References 23 publications

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“…The results presented here show that mGluR 7A and Ca 2ϩ /CaM form a classical wraparound CaM⅐receptor complex with a 1:1 stoichiometry and a basic 1-8-14 receptor-binding motif similar to that found in smooth muscle myosin light chain kinase. In addition, our structural data indicate that Ca 2ϩ /CaM binding to mGluR 7A includes interactions with both Ser 862 , a target site for phosphorylation by protein kinase C (13,24,25), and the G␤␥ recognition motif, and thus support the view that CaM regulates signal transduction in an activity-dependent manner by competition for receptor-binding sites (15).…”

supporting

confidence: 74%

“…The mGluR 7A sequence is unusual in that instead of a basic residue a serine (Ser 862 ) precedes the phenylalanine, which is the site of phosphorylation by protein kinase C (13,24). Phosphorylation at equivalent sites in other binding sequences has been shown to greatly reduce the affinity for Ca 2ϩ / CaM.…”

Section: Structural Analysis Of the Mglur 7a-c Cam Interaction-mentioning

confidence: 99%

“…A cluster of positively charged amino acids and a conserved serine residue (Ser 862 ) precede a hydrophobic motif containing the actual CaM-binding sequence. Based on binding experiments and sequence alignment, we tentatively proposed a 1-5-10 CaM-binding motif for the C terminus of mGluR 7 (13,14). Mutational analysis of the CaM-binding motif revealed that it overlaps with the interaction site for G-protein ␤␥-subunits (G␤␥) (12), suggesting that Ca 2ϩ /CaM may regulate signal transduction of the receptor.…”

mentioning

confidence: 98%

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Structural Determinants of Calmodulin Binding to the Intracellular C-terminal Domain of the Metabotropic Glutamate Receptor 7A

Scheschonka

Findlow

Schemm

et al. 2008

Journal of Biological Chemistry

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supporting

confidence: 74%

Section: Structural Analysis Of the Mglur 7a-c Cam Interaction-mentioning

confidence: 99%

mentioning

confidence: 98%

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Structural Determinants of Calmodulin Binding to the Intracellular C-terminal Domain of the Metabotropic Glutamate Receptor 7A

Scheschonka

Findlow

Schemm

et al. 2008

Journal of Biological Chemistry

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“…Previous work has demonstrated that CaM binding to the receptor third intracellular loops can attenuate the interactions between G␣ i and several receptors, including the 5-HT 1A receptor (36), -opioid receptor (34), D 2 dopamine receptor (33), and the group III metabotropic glutamate receptor, mGluR7a (66,67). New evidence in the current report suggests that CaM binding to the second intracellular loop of the 5-HT 2A receptor likely modulates coupling to heterotrimeric G proteins, most likely G␣ q/11 and/or G␣ 12/13 subunits.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Calmodulin with the Serotonin 5-Hydroxytryptamine2A Receptor

Turner

Raymond

2005

Journal of Biological Chemistry

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The 5 1 receptor is a prototypical G protein-coupled receptor (GPCR) that plays diverse roles in both the central nervous system and peripheral vasculature. In the central nervous system these receptors are widely distributed, being expressed in the neocortex, claustrum, mammilary nuclei, basal ganglia, and anterior cingulate cortex (1). 5-HT 2A receptors are also highly expressed in vascular smooth muscle and renal mesangial cells, where they mediate contraction and proliferation (2-4), and platelets, where they contribute to aggregation and adherence (5), as well as in kidney (6) and skeletal muscle (7,8). The heterogeneous expression of the 5-HT 2A receptor is accompanied by a diverse array of pathophysiological implications for 5-HT 2A receptor signaling, including roles in sleep, hallucinogenesis, schizophrenia, appetite control, neuroendocrine secretions, hypertension, and depression (9 -12). The 5-HT 2A receptor is involved in the mechanism of action of hallucinogens, atypical neuroleptics, antidepressants, and other psychoactive drugs.5-HT 2A receptors signal primarily through heterotrimeric proteins of the G q/11 subfamily to the activation of phospholipase C, and the subsequent formation of diacylglycerol and activation of protein kinase C (13-15). Other second messengers and effectors regulated by the 5-HT 2A receptor include phospholipase A 2 (16 -18), phospholipase D (19), Ca 2ϩ channels (20 -22), reactive oxygen and nitrogen species (23, 24), and Na ϩ /H ϩ exchange (25,26). In essentially all cases, activation of downstream signaling molecules has been shown to be mediated by heterotrimeric G proteins.Calmodulin (CaM) is a small (148 amino acids, ϳ17 kDa), soluble protein, which functions as the major calcium sensor in most cells (27). As a prototypical member of the EF-hand family of Ca 2ϩ -binding proteins, CaM can bind up to four Ca 2ϩ ions, which subsequently extend the protein to expose hydrophobic patches capable of binding cellular targets (28,29). These targets number well over one hundred and include enzymes, ion channels, transcription factors, and cytoskeletal proteins. Recently, CaM has been shown to bind to several plasma membrane receptors, including the epidermal growth factor receptor, platelet glycoprotein VI, and some GPCRs (30, 31). The first GPCR that was shown to interact with CaM was the metabotropic glutamate subtype 5 receptor, which contains a * This work was supported by Department of Veterans Affairs Merit and Research Enhancement Award Program awards (to J. R. R.), by National Institutes of Health Grants GM08716 (to J. H. T.) and DK52448 and GM63909 (to J. R. R.), by a predoctoral fellowship from the American Heart Association, Mid-Atlantic Affiliate (Grant 0215195U to J. H. T.), and by laboratory endowments jointly supported by the Medical University of South Carolina, Division of Nephrology and Dialysis Clinics, Inc. (to J. R. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked...

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“…PKC phosphorylated Ser-881 in mGluR5, located in the PP1␥1/2 binding motifs identified in this study. PKC was also linked to mGluR7b via PICK1 (27), and PKC phosphorylation of the proximal C-terminal domain, identical between mGluR7a and mGluR7b, was shown (51).…”

Section: Discussionmentioning

confidence: 99%

Group I Metabotropic Glutamate Receptors Bind to Protein Phosphatase 1C

Croci

Sticht

Brandstätter

et al. 2003

Journal of Biological Chemistry

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The modulation of neurotransmitter receptors by kinases and phosphatases represents a key mechanism in controlling synaptic signal transduction. However, molecular determinants involved in the specific targeting and interactions of these enzymes are largely unknown. Here, we identified both catalytic ␥-isoforms of protein phosphatase 1C (PP1␥1 and PP1␥2) as binding partners of the group I metabotropic glutamate receptors type 1a, 5a, and 5b in yeast cells and pull-down assays, using recombinant and native protein preparations. The tissue distribution of interacting proteins was compared, and protein phosphatase 1C was detected in dendrites of retinal bipolar cells expressing the respective interacting glutamate receptors. We mapped interacting domains within binding partners and identified five amino acids in the intracellular C termini of the metabotropic glutamate receptors type 1a, 5a, 5b, and 7b being both necessary and sufficient to bind protein phosphatase 1C. Furthermore, we show a dose-dependent competition of these C termini in binding the enzyme. Based on our data, we investigated the structure of the identified amino acids bound to protein phosphatase 1C by homology-based molecular modeling. In summary, these results provide a molecular description of the interaction between protein phosphatase 1C and metabotropic glutamate receptors and thereby increase our understanding of glutamatergic signal transduction.The correct targeting and localization of proteins to synaptic specializations represents an important biological mechanism to regulate neuronal excitability. Increasing evidence underlines the importance of macromolecular signaling complexes, where functionally related proteins such as ion channels, neurotransmitters receptors, kinases, and phosphatases are arranged in close vicinity and are physically anchored to the synaptic cytoskeleton. Therefore, identification and characterization of interactions between synaptically localized proteins adds substantially to our understanding of molecular mechanisms of neurotransmission.Receptors for glutamate are divided in ion channel-associated (ionotropic) receptors of the AMPA-, Kainate-, and NMDAtype and in G-protein coupled (metabotropic) receptors. Although ionotropic glutamate receptors mediate fast synaptic transmission, metabotropic glutamate receptors (mGluRs) 1 modulate neuronal excitability and development, synaptic plasticity, transmitter release, and memory function using a variety of intracellular second messenger systems (1). The eight known members of this protein family are sub-divided into three groups, based on sequence homology, associated second messenger systems, and pharmacological properties (2). mGluR1 and mGluR5 (group I) stimulate phospholipase C, are selectively activated by quisqualate, and are generally expressed perisynaptically at postsynaptic sites (3-7). mGluR2 and mGluR3 (group II) are negatively coupled to adenylyl cyclase and do not show a specific preference for pre-or postsynaptic neurons (8 -10). mGluR4, mGluR7, and...

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PKC phosphorylation of a conserved serine residue in the C‐terminus of group III metabotropic glutamate receptors inhibits calmodulin binding

Cited by 48 publications

References 23 publications

Structural Determinants of Calmodulin Binding to the Intracellular C-terminal Domain of the Metabotropic Glutamate Receptor 7A

Structural Determinants of Calmodulin Binding to the Intracellular C-terminal Domain of the Metabotropic Glutamate Receptor 7A

Interaction of Calmodulin with the Serotonin 5-Hydroxytryptamine2A Receptor

Group I Metabotropic Glutamate Receptors Bind to Protein Phosphatase 1C

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