Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Jiang, Lily I.; Collins, Julie; Davis, Richard M.; Fraser, Iain D. C.; Sternweis, Paul C.

doi:10.1074/jbc.m803281200

Cited by 53 publications

(51 citation statements)

References 46 publications

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“…Intracellular cAMP responses to isoproterenol or bile acid treatment [cholic acid (CA), taurocholic acid (TCA), glycocholic acid (GCA), chenoxycholic acid (CDCA), taurine chenoxycholic acid (TCDCA), glycine chenoxycholic acid (GCDCA)], (all bile acids were purchased from Sigma) were assessed as previously described (25,26). To generate a Col/BA complex, Colesevelam was hydrated in simulated intestinal fluid as previously described (18).…”

Section: Methodsmentioning

confidence: 99%

“…For real-time measurement of cAMP responses in HEK293 cells, we generated a HEK cell line that stably expressed the cAMP bioluminescence resonance energy transfer (BRET) sensor, CAMYEL (25), and the human TGR5 receptor (TGR5-BRET cells). Functionality of the TGR5 receptor was assessed in the cell lines stably expressing the receptor by testing cAMP production in response to stimulation with bile acids.…”

Section: Methodsmentioning

confidence: 99%

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Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice

Potthoff

Potts

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

141

130

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Potthoff MJ, Potts A, He T, Duarte JA, Taussig R, Mangelsdorf DJ, Kliewer SA, Burgess SC. Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice. Am J Physiol Gastrointest Liver Physiol 304: G371-G380, 2013. First published December 20, 2012; doi:10.1152/ajpgi.00400.2012.-Bile acid sequestrants are nonabsorbable resins designed to treat hypercholesterolemia by preventing ileal uptake of bile acids, thus increasing catabolism of cholesterol into bile acids. However, sequestrants also improve hyperglycemia and hyperinsulinemia through less characterized metabolic and molecular mechanisms. Here, we demonstrate that the bile acid sequestrant, colesevelam, significantly reduced hepatic glucose production by suppressing hepatic glycogenolysis in diet-induced obese mice and that this was partially mediated by activation of the G protein-coupled bile acid receptor TGR5 and glucagon-like peptide-1 (GLP-1) release. A GLP-1 receptor antagonist blocked suppression of hepatic glycogenolysis and blunted but did not eliminate the effect of colesevelam on glycemia. The ability of colesevelam to induce GLP-1, lower glycemia, and spare hepatic glycogen content was compromised in mice lacking TGR5. In vitro assays revealed that bile acid activation of TGR5 initiates a prolonged cAMP signaling cascade and that this signaling was maintained even when the bile acid was complexed to colesevelam. Intestinal TGR5 was most abundantly expressed in the colon, and rectal administration of a colesevelam/bile acid complex was sufficient to induce portal GLP-1 concentration but did not activate the nuclear bile acid receptor farnesoid X receptor (FXR). The beneficial effects of colesevelam on cholesterol metabolism were mediated by FXR and were independent of TGR5/GLP-1. We conclude that colesevelam administration functions through a dual mechanism, which includes TGR5/GLP-1-dependent suppression of hepatic glycogenolysis and FXR-dependent cholesterol reduction. bile acids; glucagon-like peptide-1; TGR5; diabetes-induced obesity; FGF-15; FXR BILE ACID SEQUESTRANTS ARE orally administered nonabsorbable resins designed to treat hypercholesterolemia (23) but that have unexpected beneficial effects on glycemia in subjects with type 2 diabetes mellitus (T2DM) (17). This observation has been confirmed in multiple human studies, animal models, and with a variety of different bile acid binding resins (reviewed in Ref. 41). Colesevelam is a bile acid sequestrant used to treat T2DM, but the mechanisms by which it and other sequestrants act on glucose metabolism are incompletely understood. Inasmuch as colesevelam passes through the digestive track unaltered, its efficacy on both cholesterol and glucose metabolism are thought to originate from its high bile acid-binding affinity.Bile acids are amphipathic molecules synthesized in liver, stored in the gallbladder, and secreted into the small intestine to facilitate dietary lipid absorption (48). Ileal bile acid reabsorption and uptake by the liver is nearly q...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice

Potthoff

Potts

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

141

130

View full text Add to dashboard Cite

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“…Following stimulation with thrombin, GEF-H1 was immunoprecipitated from lysates of starved HEK293T cells expressing the rgRGS domain (to sequester Ga 12/13 ) 18,19 and/or bARKct (to block Gb) 16 . The resulting immune complexes were probed for endogenous DIC as a marker of GEF-H1 localization to the microtubule-associated dynein-protein complex.…”

Section: Ga or Gb Is Sufficient To Release Gef-h1 From Microtubulesmentioning

confidence: 99%

Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1

et al. 2014

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“…Because the Ga 13 -mediated inhibition of AhR explicates in a RhoA-independent manner, what happens to Ga 13 signalling is at present unknown. However, it is interesting to note that there are some evidences reporting the involvement of the Ga 13 pathway in the regulation of cAMP responses (Jiang et al 2007(Jiang et al , 2008. Specifically, the synergistic regulation of cAMP synthesis by the Ga s and Ga 13 pathways was shown to be mediated by a specific isoform of adenylyl cyclase, termed AC7 (Jiang et al 2008).…”

Section: G Proteinsmentioning

confidence: 99%

AIP and its interacting partners

Trivellin¹,

Korbonits²

2011

Journal of Endocrinology

130

119

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Germline mutations in the aryl hydrocarbon receptorinteracting protein gene (AIP) predispose to young-onset pituitary tumours, most often to GH-or prolactin-secreting adenomas, and most of these patients belong to familial isolated pituitary adenoma families. The molecular pathway initiated by the loss-of-function AIP mutations leading to pituitary tumour formation is unknown. AIP, a co-chaperone of heat-shock protein 90 and various nuclear receptors, belongs to the family of tetratricopeptide repeat (TPR)-containing proteins. It has three antiparallel a-helix motifs (TPR domains) that mediate the interaction of AIP with most of its partners. In this review, we summarise the known interactions of AIP described so far. The identification of AIP partners and the understanding of how AIP interacts with these proteins might help to explain the specific phenotype of the families with heterozygous AIP mutations, to gain deeper insight into the pathological process of pituitary tumour formation and to identify novel drug targets.

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Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Cited by 53 publications

References 46 publications

Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice

Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice

Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1

AIP and its interacting partners

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