Spatial resolution of cAMP signaling by soluble adenylyl cyclase

G protein–coupled receptor signaling starts at the plasma membrane and continues at endosomal stations. In this issue, Inda et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201512075) show that different forms of adenylyl cyclase are activated at the plasma membrane versus endosomes, providing a rationale for the spatial encoding of cAMP signaling.

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Regulatory Role of G Protein-coupled Receptors in Pancreatic Cancer Development and Progression

Current Medicinal Chemistry ◽

10.2174/0929867324666170303121708 ◽

2018 ◽

Vol 25 (22) ◽

pp. 2566-2575 ◽

Cited By ~ 7

Author(s):

Hildegard M. Schuller

Keyword(s):

Risk Factors ◽

Pancreatic Cancer ◽

Side Effects ◽

G Protein ◽

Psychological Stress ◽

Camp Signaling ◽

Receptor Signaling ◽

Beta Adrenergic ◽

Cancer Intervention ◽

G Protein Coupled

Background: Pancreatic cancer is the fourth leading cause of cancer deaths with rising incidence and a high mortality rate. Smoking, psychological stress, diabetes, pancreatitis and alcohol abuse are known risk factors for pancreatic cancer. Objective: Targeting G protein-coupled receptor signaling for the prevention and therapy of pancreatic cancer. Method: Review of published literature. Results and Conclusion: All known risk factors for pancreatic cancer cause hyperactive cyclic adenosine monophosphate (cAMP) signaling via cancer stimulating Gαs-coupled beta-adrenergic and prostaglandin E2 receptors and/or by suppressing signaling via inhibitory Gαi-coupled GABAB-receptors. Psychological stress in mice promotes the progression of pancreatic cancer xenografts via stress neurotransmitter-mediated increase in betaadrenergic signaling and suppression of GABA while stress reduction inhibits pancreatic cancer by reversing these effects. The activation of Gαi-coupled GABAB-receptor signaling by treatment with GABA, inhibition of beta-adrenergic signaling by a beta-blocker and/or suppression of Gαs-coupled PGE2 receptor signaling by a cyclooxygenase (COX) inhibitor prevent the development and progression of pancreatic cancer induced in hamsters by carcinogenic nitrosamines and in transgenic mice. The re-purposing of cardiovascular therapeutics (beta-blockers, COX-2 inhibitors, Ca2+-channel blockers) that inhibit betaadrenergic and PGE2 signaling for pancreatic cancer intervention is problematic due to undesirable side effects under chronic treatment protocols. To avoid such side effects while effectively reducing excessive cAMP signaling, nutritional GABA supplementation or positive allosteric modulators (PAMs) of Gαi-coupled receptors (GABAB-Rs) currently in clinical trials for the treatment of addiction should be explored for pancreatic cancer intervention.

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Role of soluble adenylyl cyclase in the heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00701.2011 ◽

2012 ◽

Vol 302 (3) ◽

pp. H538-H543 ◽

Cited By ~ 19

Author(s):

Jonathan Chen ◽

Lonny R. Levin ◽

Jochen Buck

Keyword(s):

Endothelial Cells ◽

Plasma Membrane ◽

Adenylyl Cyclase ◽

G Protein ◽

Nutrient Utilization ◽

Soluble Adenylyl Cyclase ◽

Atp Production ◽

Downstream Effector ◽

Subsequent Activation ◽

Unique Source

This review discusses the potential place of soluble adenylyl cyclase (sAC) in the framework of signaling in the cardiovascular system. cAMP has been studied as a critical and pleiotropic second messenger in cardiomyocytes, endothelial cells, and smooth muscle vascular cells for many years. It is involved in the transduction of signaling by catecholamines, prostaglandins, adenosine, and glucagon, just to name a few. These hormones can act via cAMP by binding to a G protein-coupled receptor on the plasma membrane with subsequent activation of a heterotrimeric G protein and its downstream effector, transmembrane adenylyl cyclase. This has long been the canonical standard for cAMP production in a cell. However, the relatively recent discovery of a unique source of cAMP, sAC, creates the potential for a shift in this signaling paradigm. In fact, sAC has been shown to play a role in apoptosis in coronary endothelial cells and cardiomyocytes. Additionally, it links nutrient utilization with ATP production in the liver and brain, which suggests one of many potential roles for sAC in cardiac function. The possibility of producing cAMP from a source distal to the plasma membrane provides a critical new building block for reconstructing the cellular signaling infrastructure.

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Regulation of G protein‐coupled receptor signaling by plasma membrane organization and endocytosis

Traffic ◽

10.1111/tra.12628 ◽

2018 ◽

Cited By ~ 12

Author(s):

Zara Y. Weinberg ◽

Manojkumar A. Puthenveedu

Keyword(s):

Plasma Membrane ◽

G Protein ◽

Receptor Signaling ◽

Membrane Organization ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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Different cAMP sources are critically involved in G protein–coupled receptor CRHR1 signaling

The Journal of Cell Biology ◽

10.1083/jcb.201512075 ◽

2016 ◽

Vol 214 (2) ◽

pp. 181-195 ◽

Cited By ~ 35

Author(s):

Carolina Inda ◽

Paula A. dos Santos Claro ◽

Juan J. Bonfiglio ◽

Sergio A. Senin ◽

Giuseppina Maccarrone ◽

...

Keyword(s):

Plasma Membrane ◽

Cyclic Amp ◽

G Protein ◽

Adenylyl Cyclases ◽

Alternative Source ◽

Soluble Adenylyl Cyclase ◽

Extracellular Signal Regulated Kinase ◽

Signaling Mechanisms ◽

Extracellular Signal ◽

G Protein Coupled

Corticotropin-releasing hormone receptor 1 (CRHR1) activates G protein–dependent and internalization-dependent signaling mechanisms. Here, we report that the cyclic AMP (cAMP) response of CRHR1 in physiologically relevant scenarios engages separate cAMP sources, involving the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). cAMP produced by tmACs and sAC is required for the acute phase of extracellular signal regulated kinase 1/2 activation triggered by CRH-stimulated CRHR1, but only sAC activity is essential for the sustained internalization-dependent phase. Thus, different cAMP sources are involved in different signaling mechanisms. Examination of the cAMP response revealed that CRH-activated CRHR1 generates cAMP after endocytosis. Characterizing CRHR1 signaling uncovered a specific link between CRH-activated CRHR1, sAC, and endosome-based signaling. We provide evidence of sAC being involved in an endocytosis-dependent cAMP response, strengthening the emerging model of GPCR signaling in which the cAMP response does not occur exclusively at the plasma membrane and introducing the notion of sAC as an alternative source of cAMP.

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