| pubmed-article:19737913 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:19737913 | lifeskim:mentions | umls-concept:C0332307 | lld:lifeskim |
| pubmed-article:19737913 | lifeskim:mentions | umls-concept:C0037083 | lld:lifeskim |
| pubmed-article:19737913 | lifeskim:mentions | umls-concept:C0206529 | lld:lifeskim |
| pubmed-article:19737913 | lifeskim:mentions | umls-concept:C1280500 | lld:lifeskim |
| pubmed-article:19737913 | lifeskim:mentions | umls-concept:C1446409 | lld:lifeskim |
| pubmed-article:19737913 | lifeskim:mentions | umls-concept:C1710082 | lld:lifeskim |
| pubmed-article:19737913 | lifeskim:mentions | umls-concept:C0596235 | lld:lifeskim |
| pubmed-article:19737913 | lifeskim:mentions | umls-concept:C1709060 | lld:lifeskim |
| pubmed-article:19737913 | lifeskim:mentions | umls-concept:C1548602 | lld:lifeskim |
| pubmed-article:19737913 | pubmed:issue | 6 | lld:pubmed |
| pubmed-article:19737913 | pubmed:dateCreated | 2009-11-25 | lld:pubmed |
| pubmed-article:19737913 | pubmed:abstractText | Agonist stimulation of the type 5 metabotropic glutamate (mGlu5) receptor initiates robust oscillatory changes in cytosolic Ca2+ concentration ([Ca2+]i) in single cells by rapid, repeated cycles of phosphorylation/dephosphorylation of the mGlu5 receptor, involving protein kinase C and as-yet-unspecified protein phosphatase activities. An emergent property of this type of Ca2+ oscillation-generating mechanism (termed "dynamic uncoupling") is that once a threshold concentration has been reached to initiate the Ca2+ oscillation, its frequency is largely insensitive to further increases in orthosteric agonist concentration. Here, we report the effects of positive allosteric modulators (PAMs) on the patterns of single-cell Ca2+ signaling in recombinant and native mGlu5 receptor-expressing systems. In a Chinese hamster ovary cell-line (CHO-lac-mGlu5a), none of the mGlu5 receptor PAMs studied [3,3'-difluorobenzaldazine (DFB), N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl]phenyl}-2-hydroxy-benzamide (CPPHA), 3-cyano-N-(1, 3-diphenyl-1H-prazol-5-yl)benzamide (CDPPB), S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidinl-1-yl}-methanone (ADX47273)], stimulated a Ca2+ response when applied alone, but each PAM concentration-dependently increased the frequency, without affecting the amplitude, of Ca2+ oscillations induced by glutamate or quisqualate. Therefore, PAMs can cause graded increases (and negative allosteric modulator-graded decreases) in the Ca2+ oscillation frequency stimulated by orthosteric agonist. Initial data in rat cerebrocortical astrocytes demonstrated that similar effects of PAMs could be observed in a native cell background, although at high orthosteric agonist concentrations, PAM addition could much more often be seen to drive rapid Ca2+ oscillations into peak-plateau responses. These data demonstrate that allosteric modulators can "tune" the Ca2+ oscillation frequency initiated by mGlu5 receptor activation, and this might allow pharmacological modification of the downstream processes (e.g., transcriptional regulation) that is unachievable through orthosteric ligand interactions. | lld:pubmed |
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| pubmed-article:19737913 | pubmed:language | eng | lld:pubmed |
| pubmed-article:19737913 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19737913 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:19737913 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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| pubmed-article:19737913 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:19737913 | pubmed:month | Dec | lld:pubmed |
| pubmed-article:19737913 | pubmed:issn | 1521-0111 | lld:pubmed |
| pubmed-article:19737913 | pubmed:author | pubmed-author:WatsonJeannet... | lld:pubmed |
| pubmed-article:19737913 | pubmed:author | pubmed-author:ChallissR A... | lld:pubmed |
| pubmed-article:19737913 | pubmed:author | pubmed-author:BradleySophie... | lld:pubmed |
| pubmed-article:19737913 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:19737913 | pubmed:volume | 76 | lld:pubmed |
| pubmed-article:19737913 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:19737913 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:19737913 | pubmed:pagination | 1302-13 | lld:pubmed |
| pubmed-article:19737913 | pubmed:dateRevised | 2010-9-27 | lld:pubmed |
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