Aldosterone stimulates the cardiac sodium/bicarbonate cotransporter via activation of the g protein-coupled receptor gpr30

Giusti, Verónica Celeste De; Orlowski, Alejandro; Ciancio, María Carolina; Espejo, María Sofía; Gonano, Luis Alberto; Caldiz, Claudia Irma; Petroff, Martín Gerardo Vila; Villa‐Abrille, María C.; Aiello, Ernesto Alejandro

doi:10.1016/j.yjmcc.2015.10.024

Cited by 32 publications

(38 citation statements)

References 56 publications

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“…We have previously demonstrated that Ald stimulates NBC in adult rat ventricular myocytes, accelerating pH i recovery during acidosis, 9 as also shown herein in Figure 1A. We performed a double ammonium pulse in HCO 3 ¡ buffered solution in the presence of the blocker of the NHE1 HOE642 (10 mM).…”

Section: Nbce1 Is the Nbc Isoform Stimulated By Ald And Gpr30 Activationmentioning

confidence: 67%

“…9 Herein, we have identified that the NBC isoform implicated in such effect is NBCe1. Using specific NBCe1 inhibitory antibodies we demonstrated that Ald does not affect NBCn1 activity.…”

Section: Discussionmentioning

confidence: 93%

“…1A upper panel), the average HCO 3 ¡ influx (J HCO3-) (Fig. 1A lower panel) or the percentage effect of Ald on J HCO3-corrected by the normal attenuation of the recovery rate of the second pulse 9 (Fig. 1C), Ald was able to enhance NBC mediated pH i recovery from acidosis in a clear significant manner.…”

Section: Nbce1 Is the Nbc Isoform Stimulated By Ald And Gpr30 Activationmentioning

confidence: 85%

“…7,8 Consistently, we have recently demonstrated that Ald activates GPR30 in adult rat ventricular myocytes, which transactivates the epidermal growth factor receptor (EGFR) and in turn triggers a reactive oxygen species (ROS)-and PI3K/AKT-dependent pathway, leading to the stimulation of NBC. 9 Nevertheless, the NBC isoform involved in the stimulatory effect of Ald remains unknown. Thus, in this addendum to that previous study, 9 we investigated which was the NBC isoform involved in the Ald/GPR30-induced NBC activation.…”

Section: Introductionmentioning

confidence: 99%

“…9 Nevertheless, the NBC isoform involved in the stimulatory effect of Ald remains unknown. Thus, in this addendum to that previous study, 9 we investigated which was the NBC isoform involved in the Ald/GPR30-induced NBC activation.…”

Section: Introductionmentioning

confidence: 99%

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The cardiac electrogenic sodium/bicarbonate cotransporter (NBCe1) is activated by aldosterone through the G protein-coupled receptor 30 (GPR 30)

et al. 2016

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The sodium/bicarbonate cotransporter (NBC) transports extracellular Na C and HCO 3 ¡ into the cytoplasm upon intracellular acidosis, restoring the acidic pH i to near neutral values. Two different NBC isoforms have been described in the heart, the electroneutral NBCn1 (1Na C :1HCO 3 ¡ ) and the electrogenic NBCe1 (1Na C :2HCO 3 ¡ ). Certain non-genomic effects of aldosterone (Ald) were due to an orphan G protein-couple receptor 30 (GPR30). We have recently demonstrated that Ald activates GPR30 in adult rat ventricular myocytes, which transactivates the epidermal growth factor receptor (EGFR) and in turn triggers a reactive oxygen species (ROS)-and PI3K/AKT-dependent pathway, leading to the stimulation of NBC. The aim of this study was to investigate the NBC isoform involved in the Ald/GPR30-induced NBC activation. Using specific NBCe1 inhibitory antibodies (a-L3) we demonstrated that Ald does not affect NBCn1 activity. Ald was able to increase NBCe1 activity recorded in isolation. Using immunofluorescence and confocal microscopy analysis we showed in this work that both NBCe1 and GPR30 are localized in t-tubules. In conclusion, we have demonstrated that NBCe1 is the NBC isoform activated by Ald in the heart.

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Section: Nbce1 Is the Nbc Isoform Stimulated By Ald And Gpr30 Activationmentioning

confidence: 67%

“…9 Herein, we have identified that the NBC isoform implicated in such effect is NBCe1. Using specific NBCe1 inhibitory antibodies we demonstrated that Ald does not affect NBCn1 activity.…”

Section: Discussionmentioning

confidence: 93%

Section: Nbce1 Is the Nbc Isoform Stimulated By Ald And Gpr30 Activationmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The cardiac electrogenic sodium/bicarbonate cotransporter (NBCe1) is activated by aldosterone through the G protein-coupled receptor 30 (GPR 30)

et al. 2016

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The reduced myofilament responsiveness to calcium contributes to the negative force-frequency relationship in rat cardiomyocytes: role of reactive oxygen species and p-38 map kinase

Espejo

Aiello

Sepúlveda

et al. 2017

Pflugers Arch - Eur J Physiol

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The force-frequency relationship (FFR) is an important intrinsic regulatory mechanism of cardiac contractility. However, a decrease (negative FFR) or no effect (flat FFR) on contractile force in response to an elevation of heart rate is present in the normal rat or in human heart failure. Reactive oxygen species (ROS) can act as intracellular signaling molecules activating diverse kinases as calcium-calmodulin-dependent protein kinase II (CaMKII) and p-38 MAP kinase (p-38K). Our aim was to elucidate the intracellular molecules implicated in the FFR of isolated rat ventricular myocytes. The myocytes were field-stimulated via two-platinum electrodes. Sarcomere length was recorded with a video camera. Ca transients and intracellular pH were recorded by epifluorescence. Increasing frequency from 0.5 to 3 Hz decreased cell shortening without changes in pH. This negative FFR was changed to positive FFR when the myocytes were pre-incubated with the ROS scavenger MPG, the NADPH oxidase blocker apocynin, or by inhibiting mitochondrial ROS production with 5-HD. Similar results were obtained when the cells were pre-incubated with the CaMKII blocker, KN-93, or the p-38K inhibitor, SB-202190. Consistently, the levels of phosphorylation of p-38K and the oxidation of CaMKII were significantly higher at 2 Hz than at 0.5 Hz. Despite the presence of positive inotropic effect during stimulation frequency enhancement, Ca transient amplitudes were reduced in MPG- and SB-202190-treated myocytes. In conclusion, our results indicate that the activation of the intracellular pathway involving ROS-CaMKII-p-38K contributes to the negative FFR of rat cardiomyocytes, likely by desensitizing the response of contractile myofilaments to Ca.

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The functional association between the sodium/bicarbonate cotransporter (NBC) and the soluble adenylyl cyclase (sAC) modulates cardiac contractility

Espejo

Orlowski

Ibañez

et al. 2019

Pflugers Arch - Eur J Physiol

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The soluble adenylyl cyclase (sAC) was identified in the heart as another source of cyclic AMP (cAMP). However, its cardiac physiological function is unknown. On the other hand, the cardiac Na + /HCO 3 − cotransporter (NBC) promotes the cellular coinflux of HCO 3 − and Na + . Since sAC activity is regulated by HCO 3 − , our purpose was to investigate the potential functional relationship between NBC and sAC in the cardiomyocyte. Rat ventricular myocytes were loaded with Fura-2, Fluo-3, or BCECF to measure Ca 2+ transient (Ca 2+ i ) by epifluorescence, Ca 2+ sparks frequency (CaSF) by confocal microscopy, or intracellular pH (pH i ) by epifluorescence, respectively. Sarcomere or cell shortening was measured with a video camera as an index of contractility. The NBC blocker S0859 (10 μM), the selective inhibitor of sAC KH7 (1 μM), and the PKA inhibitor H89 (0.1 μM) induced a negative inotropic effect which was associated with a decrease in Ca 2+ i . Since PKA increases Ca 2+ release through sarcoplasmic reticulum RyR channels, CaSF was measured as an index of RyR open probability. The generation of CaSF was prevented by KH7. Finally, we investigated the potential role of sAC activation on NBC activity. NBC-mediated recovery from acidosis was faster in the presence of KH7 or H89, suggesting that the pathway sAC-PKA is negatively regulating NBC function, consistent with a negative feedback modulation of the HCO 3 − influx that activates sAC. In summary, the results demonstrated that the complex NBC-sAC-PKA plays a relevant role in Ca 2+ handling and basal cardiac contractility.

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Aldosterone stimulates the cardiac sodium/bicarbonate cotransporter via activation of the g protein-coupled receptor gpr30

Cited by 32 publications

References 56 publications

The cardiac electrogenic sodium/bicarbonate cotransporter (NBCe1) is activated by aldosterone through the G protein-coupled receptor 30 (GPR 30)

The cardiac electrogenic sodium/bicarbonate cotransporter (NBCe1) is activated by aldosterone through the G protein-coupled receptor 30 (GPR 30)

The reduced myofilament responsiveness to calcium contributes to the negative force-frequency relationship in rat cardiomyocytes: role of reactive oxygen species and p-38 map kinase

The functional association between the sodium/bicarbonate cotransporter (NBC) and the soluble adenylyl cyclase (sAC) modulates cardiac contractility

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