Phosphorylation, compartmentalization, and cardiac function

Collins, Kerrie B.; Scott, John D.

doi:10.1002/iub.2677

Cited by 5 publications

(3 citation statements)

References 191 publications

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“…A-kinase anchoring proteins (AKAPs) represent a family of proteins whose function is to serve as scaffolding proteins for the specificity and spatiotemporal nature of cyclic nucleotide signaling [91][92][93]. They achieve this specificity by assembling multiprotein signaling complexes consisting of PKA, PDEs, and phosphatases [93].…”

Section: Discussionmentioning

confidence: 99%

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

Montoya-Durango,

Walter,

Rodriguez

et al. 2023

Biology

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Background: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, it has been shown that cAMP levels and enzymes involved in cAMP homeostasis are affected by alcohol. Although the role of cyclic nucleotide signaling is strongly implicated in several pathological pathways in liver diseases, studies describing the changes in genes regulating cyclic nucleotide metabolism in ALD are lacking. Methods: Male C57B/6 mice were used in an intragastric model of alcohol-associated steatohepatitis (ASH). Liver injury, inflammation, and fibrogenesis were evaluated by measuring plasma levels of injury markers, liver tissue cytokines, and gene expression analyses. Liver transcriptome analysis was performed to examine the effects of alcohol on regulators of cyclic AMP and GMP levels and signaling. cAMP and cGMP levels were measured in mouse livers as well as in livers from healthy human donors and patients with alcohol-associated hepatitis (AH). Results: Our results show significant changes in several phosphodiesterases (PDEs) with specificity to degrade cAMP (Pde4a, Pde4d, and Pde8a) and cGMP (Pde5a, Pde6d, and Pde9a), as well as dual-specificity PDEs (Pde1a and Pde10a) in ASH mouse livers. Adenylyl cyclases (ACs) 7 and 9, which are responsible for cAMP generation, were also affected by alcohol. Importantly, adenosine receptor 1, which has been implicated in the pathogenesis of liver diseases, was significantly increased by alcohol. Adrenoceptors 1 and 3 (Adrb), which couple with stimulatory G protein to regulate cAMP and cGMP signaling, were significantly decreased. Additionally, beta arrestin 2, which interacts with cAMP-specific PDE4D to desensitize G-protein-coupled receptor to generate cAMP, was significantly increased by alcohol. Notably, we observed that cAMP levels are much higher than cGMP levels in the livers of humans and mice; however, alcohol affected them differently. Specifically, cGMP levels were higher in patients with AH and ASH mice livers compared with controls. As expected, these changes in liver cyclic nucleotide signaling were associated with increased inflammation, steatosis, apoptosis, and fibrogenesis. Conclusions: These data strongly implicate dysregulated cAMP and cGMP signaling in the pathogenesis of ASH. Future studies to identify changes in these regulators in a cell-specific manner could lead to the development of novel targeted therapies for ASH.

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Section: Discussionmentioning

confidence: 99%

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

Montoya-Durango,

Walter,

Rodriguez

et al. 2023

Biology

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“…At specific cellular sites, AKAPs engage in direct protein-protein interactions with cAMP effectors, their substrates, and other signaling proteins such kinases and protein phosphatases. 48,49 PDEs are strategically positioned by direct interactions with cellular compartments or through protein-protein interactions, for example, with AKAPs. 32,34 PDEs are constitutively active and hence locally limit cAMP levels.…”

Section: Pde3a and Camp Signaling Compartments In Vascular Smooth Mus...mentioning

confidence: 99%

Mutations in Phosphodiesterase 3A ( PDE3A ) Cause Hypertension Without Cardiac Damage

2023

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Hypertension with brachydactyly (HTNB) represents an autosomal dominant form of hypertension. It is a rare syndrome, in which the blood pressure can rise by more than 50 mmHg. If untreated, the patients die of stroke by the age of 50 years. In HTNB, vascular smooth muscle cell proliferation is increased, vasodilation compromised, and the kidney not affected. Surprisingly, after decades of hypertension, HTNB is not associated with hypertension-induced cardiac damage. HTNB is caused by gain-of-function mutations in the phosphodiesterase 3A ( PDE3A ) gene. The mutant enzymes are hyperactive. PDE3A (phosphodiesterase 3A) hydrolyzes and thereby terminates cyclic adenosine monophosphate signaling in defined cellular compartments. The cardioprotective effect involves local changes of cyclic adenosine monophosphate signaling and inhibition of Ca 2+ reuptake into the sarcoplasmic reticulum of cardiac myocytes. This review introduces HTNB and discusses how insight into the molecular mechanisms underlying HTNB could contribute to a better understanding of blood pressure control and lead to PDE3A-directed strategies for the treatment of essential hypertension and the prevention of hypertension-induced cardiac damage. A focus will be on cAMP (cyclic adenosine monophosphate) signaling compartments.

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“…their subcellular localization, which determines the molecular targets within their reach, and their activation/inactivation kinetics, determining the duration of their actions. When it comes to cAMP/PKA microdomains, subcellular distribution is determined by a family of tethers, the A-kinase anchoring proteins (AKAPs)( 4 , 5 ). AKAPs associate specifically with the regulatory subunits of PKA (preferably RIIs) thanks to a docking and dimerization (D/D) domain located at their N-terminus( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

Phosphatases control the duration and range of cAMP/PKA microdomains

Conca,

Bayburtlu,

Vismara

et al. 2024

Preprint

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The spatiotemporal interplay between the second messenger cyclic AMP (cAMP) and its main effector, Protein Kinase A (PKA) is crucial for the pleotropic nature of this cascade. To maintain a high degree of specificity, the cAMP/PKA axis is organized into functional multiprotein complexes, called microdomains, precisely distributed within the cell. While the subcellular allocation of PKA is guaranteed by a family of tethers called A-Kinase-anchoring Proteins (AKAPs), the mechanisms underlying the efficient confinement of a microdomain’s functional effects are not fully understood. Here we used FRET-based sensors to detect cAMP levels and PKA-dependent phosphorylation within specific subcellular compartments and found that, while free cAMP is responsible for the activation of local PKA enzymes, the dephosphorylating actions of phosphatases dictate the duration of the microdomain’s effects. To test the range of action of PKA microdomains we used rigid aminoacidic nanorulers to distance our FRET sensors from their original location for 10 or 30 nm. Interestingly, we established that cAMP levels do not affect the spatial range of the microdomain while on the contrary, phosphatase activity acts as the main functional boundary for phosphorylated PKA targets. Our findings contribute to the design of a picture where two microdomain-forming events have distinct roles. Cyclic AMP elevations trigger the initial activation of subcellular PKA moieties, while the temporal and spatial extent of the PKA’s actions is regulated by phosphatases.

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Phosphorylation, compartmentalization, and cardiac function

Cited by 5 publications

References 191 publications

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

Mutations in Phosphodiesterase 3A ( PDE3A ) Cause Hypertension Without Cardiac Damage

Phosphatases control the duration and range of cAMP/PKA microdomains

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