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Purinergic signaling is essential for full Psickle activation by hypoxia and by normoxic acid pH in mature human sickle red cells and in vitro-differentiated cultured human sickle reticulocytes

  • Signaling and cell physiology
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Abstract

Paracrine ATP release by erythrocytes has been shown to regulate endothelial cell function via purinergic signaling, and this erythoid-endothelial signaling network is pathologically dysregulated in sickle cell disease. We tested the role of extracellular ATP-mediated purinergic signaling in the activation of Psickle, the mechanosensitive Ca2+-permeable cation channel of human sickle erythrocytes (SS RBC). Psickle activation increases intracellular [Ca2+] to stimulate activity of the RBC Gardos channel, KCNN4/KCa3.1, leading to cell shrinkage and accelerated deoxygenation-activated sickling.

We found that hypoxic activation of Psickle recorded by cell-attached patch clamp in SS RBC is inhibited by extracellular apyrase, which hydrolyzes extracellular ATP. Hypoxic activation of Psickle was also inhibited by the pannexin-1 inhibitor, probenecid, and by the P2 antagonist, suramin. A Psickle-like activity was also activated in normoxic SS RBC (but not in control red cells) by bath pH 6.0. Acid-activated Psickle-like activity was similarly blocked by apyrase, probenecid, and suramin, as well as by the Psickle inhibitor, Grammastola spatulata mechanotoxin-4 (GsMTx-4).

In vitro-differentiated cultured human sickle reticulocytes (SS cRBC), but not control cultured reticulocytes, also exhibited hypoxia-activated Psickle activity that was abrogated by GsMTx-4. Psickle-like activity in SS cRBC was similarly elicited by normoxic exposure to acid pH, and this acid-stimulated activity was nearly completely blocked by apyrase, probenecid, and suramin, as well as by GsMTx-4.

Thus, hypoxia-activated and normoxic acid-activated cation channel activities are expressed in both SS RBC and SS cRBC, and both types of activation appear to be mediated or greatly amplified by autocrine or paracrine purinergic signaling.

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Acknowledgements

We thank Boris Shmukler, Cristof Gruring, Elizabeth Egan, Mudit Chaand, Mischka Moechter, and Jale Manzo for technical assistance.

Funding

This work was funded by a grant from the Doris Duke Charitable Trust to Seth L. Alper and to Manoj T. Duraisingh, and by support from Quest Diagnostics to Seth L. Alper. Seth L. Alper was funded by the Doris Duke Charitable Trust and by Quest Diagnostics. Manoj Duraisingh was funded by the Doris Duke Charitable Trust.

Data and materials will be made available upon request to the corresponding author.

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Author notes

  1. Markus Ganter

    Present address: Center for Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg, Germany

  2. Selasi Dankwa

    Present address: Seattle Children’s Research Institute, Seattle, WA, 98109, USA

Authors and Affiliations

  1. Division of Nephrology, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Boston, MA, 02215, USA

    David H. Vandorpe, Alicia Rivera & Seth L. Alper

  2. Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA

    David H. Vandorpe, Alicia Rivera & Seth L. Alper

  3. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, 02115, USA

    Markus Ganter, Selasi Dankwa & Manoj Duraisingh

  4. Quest Diagnostics, Secaucus, NJ, 07094, USA

    Jay G. Wohlgemuth, Jeffrey S. Dlott & L. Michael Snyder

  5. Department of Laboratory Medicine, Boston Children’s Hospital, Boston, MA, 02115, USA

    Carlo Brugnara

  6. Department of Pathology, Harvard Medical School, Boston, MA, 02115, USA

    Carlo Brugnara

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Jay G. Wohlgemuth and Jeffrey S. Dlott are employees and shareholders of Quest Diagnostics. Seth L. Alper and L. Michael Snyder are consultants to Quest Diagnostics. Seth L. Alper and Carlo Brugnara are recipients of research funding from Quest Diagnostics.

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Physiological relevance

Purinergic signaling mediates or amplifies activation of Psickle by hypoxia and by normoxic acid pH in human sickle RBC and in cultured reticulocytes differentiated in vitro from CD34 + sickle erythroid precursors

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Vandorpe, D.H., Rivera, A., Ganter, M. et al. Purinergic signaling is essential for full Psickle activation by hypoxia and by normoxic acid pH in mature human sickle red cells and in vitro-differentiated cultured human sickle reticulocytes. Pflugers Arch - Eur J Physiol 474, 553–565 (2022). https://doi.org/10.1007/s00424-022-02665-z

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