Regulation by Ca2+-Signaling Pathways of Adenylyl Cyclases

Halls, Michelle L.; Cooper, Dermot M.F.

doi:10.1101/cshperspect.a004143

Cited by 184 publications

(159 citation statements)

References 122 publications

(134 reference statements)

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“…2 confirmed that Cch elevates [cAMP] in transfected BHK cells to levels which are comparable to those during forskolin stimulation. This cAMP response was Ca 2ϩ -dependent, further suggesting the involvement of a Ca 2ϩ /calmodulin-activated adenylyl cyclase (41). Further evidence for the involvement of PKA came from partial inhibition of the Cch response by the PKA-selective inhibitor Rp-cAMPS.…”

Section: Discussionmentioning

confidence: 92%

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Role of Tyrosine Phosphorylation in the Muscarinic Activation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Billet

Luo

Balghi

et al. 2013

Journal of Biological Chemistry

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Background:The canonical regulation of CFTR is mediated by serine/threonine phosphorylation. Results: GPCR stimulation of CFTR mutants lacking PKA/PKC sites revealed alternate pathways which involve tyrosine kinases. Conclusion: Pyk2 and Src family tyrosine kinases mediate part of CFTR stimulation by the M3 muscarinic receptor. Significance: This provides the first evidence that physiological secretagogues can activate CFTR through tyrosine phosphorylation.

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Section: Discussionmentioning

confidence: 92%

“…This mutant lacks the PKC consensus sequences on the R domain and distal NBD1, yet still responded to Cch stimulation. PKC and Ca 2ϩ can also activate the PKA pathway through stimulation of a Ca 2ϩ -dependent adenylate cyclase and cAMP synthesis (41). Indeed, cAMP measurements in Fig.…”

Section: Discussionmentioning

confidence: 96%

Role of Tyrosine Phosphorylation in the Muscarinic Activation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Billet

Luo

Balghi

et al. 2013

Journal of Biological Chemistry

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“…We have previously observed that a beta cell-specific subtype of adenylyl cyclases, adenylyl cyclase (ADCY) 8, was among the most strongly downregulated transcripts and proteins in rat and human islets exposed to elevated glucose concentrations [6]. The Ca 2+ -sensitive ADCY8 may serve as a coincidence detector as it senses glucose via increasing [Ca 2+ ] i and incretins through Gprotein coupled receptors [6][7][8]. Similar to ADCY8, ADCY1 is also stimulated by Ca 2+ [8] whereas ADCY5 and ADCY6 are inhibited by the cation [9,10].…”

Section: Introductionmentioning

confidence: 99%

Multilevel control of glucose homeostasis by adenylyl cyclase 8

et al. 2014

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Aims/hypothesis Nutrient homeostasis requires integration of signals generated by glucose metabolism and hormones. Expression of the calcium-stimulated adenylyl cyclase ADCY8 is regulated by glucose and the enzyme is capable of integrating signals from multiple pathways. It may thus have an important role in glucose-induced signalling and glucose homeostasis. Methods We used pharmacological and genetic approaches in beta cells to determine secretion and calcium metabolism. Furthermore, Adcy8 knockout mice were characterised. Results In clonal beta cells, inhibitors of adenylyl cyclases or their downstream targets reduced the glucose-induced increase in cytosolic calcium and insulin secretion. This was reproduced by knock-down of ADCY8, but not of ADCY1. These agents also inhibited glucose-induced increase in cytosolic calcium and electrical activity in primary beta cells and similar effects were observed after ADCY8 knock-down.Moreover, insulin secretion was diminished in islets from Adcy8 knockout mice. These mice were glucose intolerant after oral or intraperitoneal administration of glucose whereas their levels of glucagon-like peptide-1 remained unaltered. Finally, we knocked down ADCY8 in the ventromedial hypothalamus to evaluate the need for ADCY8 in the central regulation of glucose homeostasis. Whereas mice fed a standard diet had normal glucose levels, high-fat diet exacerbated glucose intolerance and knock-down mice were incapable of raising their plasma insulin levels. Finally we confirmed that ADCY8 is expressed in human islets. Conclusions/interpretations Collectively, our findings demonstrate that ADCY8 is required for the physiological activation of glucose-induced signalling pathways in beta cells, for glucose tolerance and for hypothalamic adaptation to a high-fat diet via regulation of islet insulin secretion.Electronic supplementary material The online version of this article (doi:10.1007/s00125-014-3445-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…Reports have suggested that PI3K is the downstream target of the Gbg complex (Thomason et al, 1994;Hazeki et al, 1998), but further studies are necessary to clarify that this mechanism is the one involved in EP4 signaling. It should be noted that the Gbg complex itself regulates AC, stimulating AC2 and AC4, inhibiting AC1 and AC8, and having inconsistent effects on AC3, AC5, AC6, and AC7 (Iwatsubo et al, 2006;Willoughby and Cooper, 2007;Halls and Cooper, 2011); this suggests that the Gbg complex affects not only the PI3K pathway but also the cAMP pathway upon activation of EP4. Unfortunately, little attention has yet been paid to this possibility.…”

Section: Signaling Pathwaysmentioning

confidence: 99%