Soluble Adenylyl Cyclase in Vascular Endothelium

Schmitz, Boris; Nedele, Johanna; Guske, Katrin; Maase, Martina; Lenders, Malte; Schelleckes, Michael; Kusche-Vihrog, Kristina; Brand, Stefan-Martin; Brand, Eva

doi:10.1161/hypertensionaha.113.02061

Cited by 23 publications

(14 citation statements)

References 48 publications

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“…sAC is an evolutionary ancient enzyme that is involved in

{HCO}_{3}^{-}

sensing from cyanobacteria to humans and has been mainly associated with ion/pH regulatory epithelia (Tresguerres et al, 2011). sAC has been demonstrated to be an important regulator of primarily active ion pumps including NKA (Schmitz et al, 2014) and V-type H + -ATPase (Tresguerres et al, 2011). Accordingly, it can be hypothesized that also in molluscs like O. vulgasis sAC has inherited the evolutionary conserved role as a regulator of acid-base homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Perfused Gills Reveal Fundamental Principles of pH Regulation and Ammonia Homeostasis in the Cephalopod Octopus vulgaris

Sung

Guh

et al. 2017

Front. Physiol.

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In contrast to terrestrial animals most aquatic species can be characterized by relatively higher blood NH4+ concentrations despite its potential toxicity to the central nervous system. Although many aquatic species excrete NH4+ via specialized epithelia little information is available regarding the mechanistic basis for NH3/NH4+ homeostasis in molluscs. Using perfused gills of Octopus vulgaris we studied acid-base regulation and ammonia excretion pathways in this cephalopod species. The octopus gill is capable of regulating ammonia (NH3/NH4+) homeostasis by the accumulation of ammonia at low blood levels (<260 μM) and secretion at blood ammonia concentrations exceeding in vivo levels of 300 μM. NH4+ transport is sensitive to the adenylyl cyclase inhibitor KH7 indicating that this process is mediated through cAMP-dependent pathways. The perfused octopus gill has substantial pH regulatory abilities during an acidosis, accompanied by an increased secretion of NH4+. Immunohistochemical and qPCR analyses revealed tissue specific expression and localization of Na+/K+-ATPase, V-type H+-ATPase, Na+/H+-exchanger 3, and Rhesus protein in the gill. Using the octopus gill as a molluscan model, our results highlight the coupling of acid-base regulation and nitrogen excretion, which may represent a conserved pH regulatory mechanism across many marine taxa.

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“…sAC is an evolutionary ancient enzyme that is involved in

{HCO}_{3}^{-}

Section: Discussionmentioning

confidence: 99%

Perfused Gills Reveal Fundamental Principles of pH Regulation and Ammonia Homeostasis in the Cephalopod Octopus vulgaris

Sung

Guh

et al. 2017

Front. Physiol.

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“…sAC, in a PKA-dependent manner, is especially involved in corticotropin-releasing hormone-mediated CREB phosphorylation and c-fos (endogenous CREB target) induction in hippocampal neuronal cells [ 82 ]. A recent study demonstrated that sAC contributes to the regulation of CREB-mediated Na + /K + -ATPase expression in the vascular endothelium and is an important regulator of endothelial stiffness [ 83 , 84 ]. Besides promoting CREB activity, sAC also regulates several other transcription factors.…”

Section: Functional Role Of Sac In Different Cellular Compartmentsmentioning

confidence: 99%

“…In alveolar epithelial cells, a high CO 2 concentration promotes the sAC-cAMP axis, which in turn induces a PKA-dependent phosphorylation of α-adducin, a component of the actin cytoskeleton, resulting in Na + /K + -ATPase endocytosis [ 95 ]. In the vascular endothelium, the role that the sAC-cAMP axis plays in Na + /K + -ATPase regulation has been demonstrated, as the inhibition of sAC (KH7 and interfering RNA) significantly decreases the mRNA and protein levels of Na + /K + -ATPase [ 84 ]. A recent study confirmed that the sAC-dependent regulation of Na + /K + -ATPase in the vascular endothelium plays an important role in endothelial stiffness [ 83 ].…”

Section: Functional Role Of Sac In Different Cellular Compartmentsmentioning

confidence: 99%

Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments

Pozdniakova

Ladilov

2018

JCDD

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Mounting evidence confirms the compartmentalized structure of evolutionarily conserved 3′–5′-cyclic adenosine monophosphate (cAMP) signaling, which allows for simultaneous participation in a wide variety of physiological functions and ensures specificity, selectivity and signal strength. One important player in cAMP signaling is soluble adenylyl cyclase (sAC). The intracellular localization of sAC allows for the formation of unique intracellular cAMP microdomains that control various physiological and pathological processes. This review is focused on the functional role of sAC-produced cAMP. In particular, we examine the role of sAC-cAMP in different cellular compartments, such as cytosol, nucleus and mitochondria.

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“…For crude protein extracts, cells were lysed in RIPA buffer containing 1% NP40 and 0.1% SDS (Carl Roth) supplemented with ‘Complete’ and ‘PhosStop’ protease/phosphatase inhibitor cocktail (Sigma Aldrich) as described 50 . Immunodetection of cellular extracts was performed using an anti-KIBRA (Santa Cruz Biotechnology; 1:500), anti-SP1 (Merck; 1:1000), anti-YAP (Santa Cruz Biotechnology; 1:1000), anti-pYAP (Ser127; Cell Signaling; 1:1000), anti-LATS1 (Merck; 1:1000), anti-pLATS1 (Thr1079; Cell Signaling; 1:500) and anti-rabbit secondary antibody (Santa Cruz Biotechnology; 1:20000 or Merck; 1:10000).…”

Section: Methodsmentioning

confidence: 99%

ZFP226 is a novel artificial transcription factor for selective activation of tumor suppressor KIBRA

Schelleckes

Schmitz²,

Lenders

et al. 2018

Sci Rep

Self Cite

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KIBRA has been suggested as a key regulator of the hippo pathway, regulating organ size, cell contact inhibition as well as tissue regeneration and tumorigenesis. Recently, alterations of KIBRA expression caused by promotor methylation have been reported for several types of cancer. Our current study aimed to design an artificial transcription factor capable of re-activating expression of the tumor suppressor KIBRA and the hippo pathway. We engineered a new gene named ‘ZFP226′ encoding for a ~23 kDa fusion protein. ZFP226 belongs to the Cys2-His2 zinc finger type and recognizes a nine base-pair DNA sequence 5′-GGC-GGC-GGC-3′ in the KIBRA core promoter P1a. ZFP226 showed nuclear localization in human immortalized kidney epithelial cells and activated the KIBRA core promoter (p < 0.001) resulting in significantly increased KIBRA mRNA and protein levels (p < 0.001). Furthermore, ZFP226 led to activation of hippo signaling marked by elevated YAP and LATS phosphorylation. In Annexin V flow cytometry assays ZFP226 overexpression showed strong pro-apoptotic capacity on MCF-7 breast cancer cells (p < 0.01 early-, p < 0.001 late-apoptotic cells). We conclude that the artificial transcription factor ZFP226 can be used for target KIBRA and hippo pathway activation. This novel molecule may represent a molecular tool for the development of future applications in cancer treatment.

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Soluble Adenylyl Cyclase in Vascular Endothelium

Cited by 23 publications

References 48 publications

Perfused Gills Reveal Fundamental Principles of pH Regulation and Ammonia Homeostasis in the Cephalopod Octopus vulgaris

Perfused Gills Reveal Fundamental Principles of pH Regulation and Ammonia Homeostasis in the Cephalopod Octopus vulgaris

Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments

ZFP226 is a novel artificial transcription factor for selective activation of tumor suppressor KIBRA

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