Differential effects of adenylyl cyclase-protein kinase A cascade on shear-induced changes of sickle cell deformability

Uğurel, Elif; Connes, Philippe; Yavas, Gokce; Eglenen, Buse; Turkay, Mine; Aksu, Ali Cenk; Renoux, Céline; Joly, Philippe; Gauthier, Alexandra; Hot, A.; Bertrand, Yves; Cannas, Giovanna; Yalçın, Özlem

doi:10.3233/ch-190563

Cited by 4 publications

(5 citation statements)

References 63 publications

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“…Although 11 different PDE families are present in various cell types, only 6 of them (PDE1, 2, 3, 4, 5, and 9) are defined in mature RBCs or erythroid precursors ( Almeida et al, 2008 ; Adderley et al, 2011 ). Non-selective inhibition of PDE by Pentoxifylline in the present study significantly increased the deformability of RBCs from SCD patients, both before and after the application of a constant shear stress for prolonged time, which confirms previous findings ( Ugurel et al, 2019 ) but contrast with another study ( Cummings and Ballas, 1990 ). A previous case report in the late seventies showed that Pentoxifylline treatment in a patient with SCD and frequent vaso-occlusive crises improved RBC deformability and decreased blood viscosity ( Keller and Leonhardt, 1979 ).…”

Section: Discussionsupporting

confidence: 89%

“…Therefore, SS 1/2 :EI max ratio should be considered and reflects the dependence of EI on SS independent of EI max alterations ( Baskurt and Meiselman, 2013 ). In our previous study, we also showed that the inhibition of AC/PKA signaling pathway resulted in a rise of RBC deformability in SCD patients ( Ugurel et al, 2019 ). AC inhibition reduces cAMP levels and suppresses PKA activation.…”

Section: Discussionmentioning

confidence: 82%

“…Indeed, ATP levels could affect AC pathway, which may participate to the decrease in RBC deformability in this disease. We have previously shown the potential role of AC pathway for the modulation of RBC deformability in SCD patients and demonstrated that the inhibition of cAMP hydrolysis by phosphodiesterases increased the deformability of RBCs from SCD patients ( Ugurel et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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A preliminary study of phosphodiesterases and adenylyl cyclase signaling pathway on red blood cell deformability of sickle cell patients

Goksel,

Ugurel,

Nader

et al. 2023

Front. Physiol.

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Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by chronic anemia, intravascular hemolysis, and the occurrence of vaso-occlusive crises due to the mechanical obstruction of the microcirculation by poorly deformable red blood cells (RBCs). RBC deformability is a key factor in the pathogenesis of SCD, and is affected by various factors. In this study, we investigated the effects of adenylyl cyclase (AC) signaling pathway modulation and different phosphodiesterase (PDE) modulatory molecules on the deformability and mechanical stress responses of RBC from SCD patients (HbSS genotype) by applying 5 Pa shear stress with an ektacytometer (LORRCA). We evaluated RBC deformability before and after the application of shear stress. AC stimulation with Forskolin had distinct effects on RBC deformability depending on the application of 5 Pa shear stress. RBC deformability was increased by Forskolin before shear stress application but decreased after 5 Pa shear stress. AC inhibition with SQ22536 and protein kinase A (PKA) inhibition with H89 increased RBC deformability before and after the shear stress application. Non-selective PDE inhibition with Pentoxifylline increased RBC deformability. However, modulation of the different PDE types had distinct effects on RBC deformability, with PDE1 inhibition by Vinpocetine increasing deformability while PDE4 inhibition by Rolipram decreased RBC deformability after the shear stress application. The effects of the drugs varied greatly between patients suggesting some could benefit from one drug while others not. Developing drugs targeting the AC signaling pathway could have clinical applications for SCD, but more researches with larger patient cohorts are needed to identify the differences in the responses of sickle RBCs.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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A preliminary study of phosphodiesterases and adenylyl cyclase signaling pathway on red blood cell deformability of sickle cell patients

Goksel,

Ugurel,

Nader

et al. 2023

Front. Physiol.

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“…However, the role of signaling mechanisms in RBC mechanical stress responses and the relevant changes in the RBC proteome had not been investigated. We previously showed that the cAMP/PKA pathway could potentially be a therapeutic approach for treating sickle cell disease due to shear-induced improvements of RBC deformability [ 31 ]. In the present study, we focused on the cAMP/PKA pathway regarding its possible effects on the RBC proteome and post-translational modifications of membrane proteins associated with the cytoskeletal structure that could determine shear-induced deformability in healthy RBCs.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies reported that the adenylyl cyclase (AC)/protein kinase A (PKA) signaling pathway could be a modulator of RBC deformability [ 28 , 29 , 30 ]. We previously showed that this signaling pathway could have roles in maintaining shear-induced deformability in patients with sickle cell disease [ 31 ]. The activation of membrane-bound AC via G protein-coupled receptors (GPCRs) triggers the AC/PKA signaling pathway, which follows the conversion of ATP into cAMP.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Analysis of the Role of the Adenylyl Cyclase–cAMP Pathway in Red Blood Cell Mechanical Responses

Uğurel

Goksel

Cilek

et al. 2022

Cells

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Red blood cell (RBC) deformability is modulated by the phosphorylation status of the cytoskeletal proteins that regulate the interactions of integral transmembrane complexes. Proteomic studies have revealed that receptor-related signaling molecules and regulatory proteins involved in signaling cascades are present in RBCs. In this study, we investigated the roles of the cAMP signaling mechanism in modulating shear-induced RBC deformability and examined changes in the phosphorylation of the RBC proteome. We implemented the inhibitors of adenylyl cyclase (SQ22536), protein kinase A (H89), and phosphodiesterase (PDE) (pentoxifylline) to whole blood samples, applied 5 Pa shear stress (SS) for 300 s with a capillary tubing system, and evaluated RBC deformability using a LORRCA MaxSis. The inhibition of signaling molecules significantly deteriorated shear-induced RBC deformability (p < 0.05). Capillary SS slightly increased the phosphorylation of RBC cytoskeletal proteins. Tyrosine phosphorylation was significantly elevated by the modulation of the cAMP/PKA pathway (p < 0.05), while serine phosphorylation significantly decreased as a result of the inhibition of PDE (p < 0.05). AC is the core element of this signaling pathway, and PDE works as a negative feedback mechanism that could have potential roles in SS-induced RBC deformability. The cAMP/PKA pathway could regulate RBC deformability during capillary transit by triggering significant alterations in the phosphorylation state of RBCs.

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Erythrocytes membrane fluidity changes induced by adenylyl cyclase cascade activation: study using fluorescence recovery after photobleaching

Semenov,

Lugovtsov,

Rodionov

et al. 2024

Eur Biophys J

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In this study, fluorescence recovery after photobleaching (FRAP) experiments were performed on RBC labeled by lipophilic fluorescent dye CM-DiI to evaluate the role of adenylyl cyclase cascade activation in changes of lateral diffusion of erythrocytes membrane lipids. Stimulation of adrenergic receptors with epinephrine (adrenaline) or metaproterenol led to the significant acceleration of the FRAP recovery, thus indicating an elevated membrane fluidity. The effect of the stimulation of protein kinase A with membrane-permeable analog of cAMP followed the same trend but was less significant. The observed effects are assumed to be driven by increased mobility of phospholipids resulting from the weakened interaction between the intermembrane proteins and RBC cytoskeleton due to activation of adenylyl cyclase signaling cascade. Graphical abstract

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Differential effects of adenylyl cyclase-protein kinase A cascade on shear-induced changes of sickle cell deformability

Cited by 4 publications

References 63 publications

A preliminary study of phosphodiesterases and adenylyl cyclase signaling pathway on red blood cell deformability of sickle cell patients

A preliminary study of phosphodiesterases and adenylyl cyclase signaling pathway on red blood cell deformability of sickle cell patients

Proteomic Analysis of the Role of the Adenylyl Cyclase–cAMP Pathway in Red Blood Cell Mechanical Responses

Erythrocytes membrane fluidity changes induced by adenylyl cyclase cascade activation: study using fluorescence recovery after photobleaching

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