Adenylyl cyclase signalling complexes – Pharmacological challenges and opportunities

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

doi:10.1016/j.pharmthera.2017.01.001

Cited by 87 publications

(78 citation statements)

References 111 publications

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“…There are 10 different isoforms of ADCYs, and their expression varies among different cell types. Out of these, nine (ADCY1-9) are plasma membrane-bound whereas ADCY10 is soluble and is present in the cytosol (Halls & Cooper, 2017). Interestingly, ADCY1, 3, and 8 are activated by Ca 2+ , while ADCY5 and 6 are inhibited by Ca 2+ (Cooper, 2015;Halls & Cooper, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Out of these, nine (ADCY1-9) are plasma membrane-bound whereas ADCY10 is soluble and is present in the cytosol (Halls & Cooper, 2017). Interestingly, ADCY1, 3, and 8 are activated by Ca 2+ , while ADCY5 and 6 are inhibited by Ca 2+ (Cooper, 2015;Halls & Cooper, 2017). Recently, Orai1 was reported to regulate cAMP generation by physically interacting with ADCY8 resulting in its activation and thereby elevation of cAMP (Willoughby et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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STIM 1 activation of adenylyl cyclase 6 connects Ca ²⁺ and cAMP signaling during melanogenesis

et al. 2018

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Endoplasmic reticulum (ER)-plasma membrane (PM) junctions form functionally active microdomains that connect intracellular and extracellular environments. While the key role of these interfaces in maintenance of intracellular Ca levels has been uncovered in recent years, the functional significance of ER-PM junctions in non-excitable cells has remained unclear. Here, we show that the ER calcium sensor protein STIM1 (stromal interaction molecule 1) interacts with the plasma membrane-localized adenylyl cyclase 6 (ADCY6) to govern melanogenesis. The physiological stimulus α-melanocyte-stimulating hormone (αMSH) depletes ER Ca stores, thus recruiting STIM1 to ER-PM junctions, which in turn activates ADCY6. Using zebrafish as a model system, we further established STIM1's significance in regulating pigmentation STIM1 domain deletion studies reveal the importance of Ser/Pro-rich C-terminal region in this interaction. This mechanism of cAMP generation creates a positive feedback loop, controlling the output of the classical αMSH-cAMP-MITF axis in melanocytes. Our study thus delineates a signaling module that couples two fundamental secondary messengers to drive pigmentation. Given the central role of calcium and cAMP signaling pathways, this module may be operative during various other physiological processes and pathological conditions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

STIM 1 activation of adenylyl cyclase 6 connects Ca ²⁺ and cAMP signaling during melanogenesis

et al. 2018

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“…It regulates a variety of cellular functions by regulating the synthesis of cyclic adenosine-3′,5′-monophosphate (cAMP), thereby participating in various pathophysiological processes in the body. 31 Studies have shown that different subtypes of AC have different associations with various diseases, and there is a nonspecific cross-coordination or antagonistic effect between the effect of each subtype effect. 32,33 Nonselective activation/inhibition contributes to many potential adverse reactions.…”

Section: Discussionmentioning

confidence: 99%

Gene expression and DNA methylation analyses suggest that immune process‐related ADCY6 is a prognostic factor of luminal‐like breast cancer

Sang

Hao

et al. 2019

J of Cellular Biochemistry

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Breast cancer is a malignant tumor that seriously threatens women's health, and luminal-like cancer subtypes account for the majority of the cases. The purpose of this study was to investigate the relationships among DNA methylation, gene expression profile, and the tumor-immune microenvironment of luminal-like breast cancer, and to identify the potential key genes that regulate immune cell infiltration in luminal-like breast cancer. The ESTIMATE algorithm was applied to calculate immune scores and stromal scores of patients with breast cancer. Kaplan-Meier curves were generated for survival analysis. The clusterProfile package was used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software. Correlations between ADCY6 expression and immune cell infiltration-related pathways were analyzed by gene set variation analysis. R software was used for the statistical analysis and figure generation. Disease-free survival was higher in the immune score-high group than it was in the immune score-low group, while the stromal score had no correlation with prognosis. There were 515 genes that differed in both gene expression and DNA methylation levels, and these genes were mainly enriched in immune process-related pathways. ADCY6 was enriched in module A of the PPI network. Patients with downregulation and hypermethylation of ADCY6 associated with a better prognosis. ADCY6 expression was negatively correlated with the activation of immune process-related signaling pathways, immune checkpoint receptors, and ligands, except for CLEC4G. DNA methylation was found to be involved in the regulation of the key cellular pathways of luminallike breast cancer immune cell infiltration. Additionally, ADCY6 was identified as a prognostic factor involved in the DNA methylation-regulated immune processes in luminal-like breast cancer. K E Y W O R D S ADCY6, DNA methylation, luminal-like breast cancer, tumor-immune microenvironment

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“…Using the P-site AC inhibitor 2′-5′-dideoxyadenosine, the authors reported on the intriguing finding that the de novo synthesis of ECM components distinctly depends on cAMP, suggesting that specific cAMP scaffolds are most likely operational in these structural lung cells (Lambers et al, 2014). It will therefore be of interest in the future to study the extent to which distinct ACs (Halls & Cooper, 2017), acting in concert with a distinct subset of PDEs, PKA, and Epac, may contribute to the differential regulation of ECM deposition. Even though such cAMP microdomains have been extensively studied in the cardiovascular system (Laudette et al, 2018;Musheshe, Schmidt, & Zaccolo, 2018), they still have to be defined in more detail in the pulmonary system.…”

Section: Players Of Camp Compartmentalization: Akaps Pka and Epacmentioning

confidence: 99%

Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

Zuo

Cattani‐Cavalieri

Musheshe

et al. 2019

British J Pharmacology

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Over the past decades, research has defined cAMP as one of the central cellular nodes in sensing and integrating multiple pathways and as a pivotal role player in lung pathophysiology. Obstructive lung disorders, such as chronic obstructive pulmonary disease (COPD), are characterized by a persistent and progressive airflow limitation and by oxidative stress from endogenous and exogenous insults. The extent of airflow obstruction depends on the relative deposition of different constituents of the extracellular matrix, a process related to epithelial‐to‐mesenchymal transition, and which subsequently results in airway fibrosis. Oxidative stress from endogenous and also from exogenous sources causes a profound worsening of COPD. Here we describe how cAMP scaffolds and their different signalosomes in different subcellular compartments may contribute to COPD. Future research will require translational studies to alleviate disease symptoms by pharmacologically targeting the cAMP scaffolds. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

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Adenylyl cyclase signalling complexes – Pharmacological challenges and opportunities

Cited by 87 publications

References 111 publications

STIM 1 activation of adenylyl cyclase 6 connects Ca ²⁺ and cAMP signaling during melanogenesis

STIM 1 activation of adenylyl cyclase 6 connects Ca ²⁺ and cAMP signaling during melanogenesis

Gene expression and DNA methylation analyses suggest that immune process‐related ADCY6 is a prognostic factor of luminal‐like breast cancer

Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

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Adenylyl cyclase signalling complexes – Pharmacological challenges and opportunities

Cited by 87 publications

References 111 publications

STIM 1 activation of adenylyl cyclase 6 connects Ca 2+ and cAMP signaling during melanogenesis

STIM 1 activation of adenylyl cyclase 6 connects Ca 2+ and cAMP signaling during melanogenesis

Gene expression and DNA methylation analyses suggest that immune process‐related ADCY6 is a prognostic factor of luminal‐like breast cancer

Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

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STIM 1 activation of adenylyl cyclase 6 connects Ca ²⁺ and cAMP signaling during melanogenesis

STIM 1 activation of adenylyl cyclase 6 connects Ca ²⁺ and cAMP signaling during melanogenesis