Dataset Information

Synthetic partial agonists reveal key steps in IP3 receptor activation.

ABSTRACT: Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are ubiquitous intracellular Ca2+ channels. IP(3) binding to the IP(3)-binding core (IBC) near the N terminus initiates conformational changes that lead to opening of a pore. The mechanisms underlying this process are unresolved. We synthesized 2-O-modified IP(3) analogs that are partial agonists of IP(3)R. These are similar to IP(3) in their interactions with the IBC, but they are less effective than IP(3) in rearranging the relationship between the IBC and the N-terminal suppressor domain (SD), and they open the channel at slower rates. IP(3)R with a mutation in the SD occupying a position similar to the 2-O substituent of the partial agonists has a reduced open probability that is similar for full and partial agonists. Bulky or charged substituents from either the ligand or the SD therefore block obligatory coupling of the IBC and the SD. Analysis of DeltaG for ligand binding shows that IP(3) is recognized by the IBC and conformational changes then propagate entirely via the SD to the pore.

SUBMITTER: Rossi AM

PROVIDER: S-EPMC2869033 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthetic partial agonists reveal key steps in IP3 receptor activation.

Rossi Ana M AM Riley Andrew M AM Tovey Stephen C SC Rahman Taufiq T Dellis Olivier O Taylor Emily J A EJ Veresov Valery G VG Potter Barry V L BV Taylor Colin W CW

Nature chemical biology 20090809 9

Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are ubiquitous intracellular Ca2+ channels. IP(3) binding to the IP(3)-binding core (IBC) near the N terminus initiates conformational changes that lead to opening of a pore. The mechanisms underlying this process are unresolved. We synthesized 2-O-modified IP(3) analogs that are partial agonists of IP(3)R. These are similar to IP(3) in their interactions with the IBC, but they are less effective than IP(3) in rearranging the relationship between ...[more]

PMID: 19668195

Similar Datasets

Project description:Although thiazolidinediones were designed as specific peroxisome proliferator-activated receptor (PPAR)-gamma-ligands, there is evidence for some off-target effects mediated by a non-PPARgamma mechanism. Previously we have shown that rosiglitazone has antiinflammatory actions not explicable by activation of PPARgamma,but possibly by the glucocorticoid receptor (GR). Rosiglitazone induces nuclear translocation both of GR-green fluorescent protein, and endogenous GR in HeLa and U20S cells but with slower kinetics than dexamethasone. Rosiglitazone also induces GR phosphorylation (Ser211), a GR ligand-binding-specific effect. Rosiglitazone drives luciferase expression from a simple glucocorticoid-response element containing reporter gene in a GR-dependent manner (EC50 4 microm), with a similar amplitude response to the partial GR agonist RU486. Rosiglitazone also inhibits dexamethasone-driven reporter gene activity (IC50 2.9 microm) in a similar fashion to RU486, suggesting partial agonist activity. Importantly we demonstrate a similar effect in PPARgamma-null cells, suggesting both GR dependence and PPARgamma independence. Rosiglitazone also activates a GAL4-GR chimera, driving a upstream activating sequence promoter, demonstrating DNA template sequence independence and furthermore enhanced steroid receptor coactivator-1-GR interaction, measured by a mammalian two-hybrid assay. Both ciglitazone and pioglitazone, structurally related to rosiglitazone, show similar effects on the GR. The antiproliferative effect of rosiglitazone is increased in U20S cells that overexpress GR, suggesting a biologically important GR-dependent component of rosiglitazone action. Rosiglitazone is a partial GR agonist, affecting GR activation and trafficking to influence engagement of target genes and affect cell function. This novel mode of action may explain some off-target effects observed in vivo. Additionally, antagonism of glucocorticoid action may contribute to the antidiabetic actions of rosiglitazone.

Dataset Information

Synthetic partial agonists reveal key steps in IP3 receptor activation.

Publications

Synthetic partial agonists reveal key steps in IP3 receptor activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure