Essential role of CD38 in platelet aggregation through the PKC-mediated internalization and activation

Mazhar Mushtaq; Maira Mahmood; Uzma Jabbar; Uh-Hyun Kim

doi:10.34172/bi.2023.27780

Essential role of CD38 in platelet aggregation through the PKC-mediated internalization and activation

Bioimpacts. 2024;14(2):27780. doi: 10.34172/bi.2023.27780. Epub 2023 Sep 30.

Authors

Mazhar Mushtaq¹, Maira Mahmood², Uzma Jabbar³, Uh-Hyun Kim⁴

Affiliations

¹ Basic Medical Sciences, Sulaiman Al Rajhi University, Al-Qaseem, Kingdom of Saudi Arabia.
² Department of Biochemistry, FMH College of Medicine and Dentistry, Lahore, Pakistan ‎.
³ Department of Biochemistry, Gujranwala Medical College, Gujranwala, Pakistan.
⁴ Department of Biochemistry, Chonbuk National University, Chonbuk, South Korea.

Abstract

Introduction: CD38 is a multifunctional enzyme with a potent Ca²⁺ mobilizing effect, cyclic ADP-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP). Here, we aimed to demonstrate the role of CD38 in platelets via protein kinase C (PKC)-mediated internalization and activation.

Methods: Mouse platelets were used in this study. Thrombin, an agonist of platelet function, provoked a prompt and long-lasting increase in intracellular Ca²⁺ concentration ([Ca²⁺]i), resulting from an interplay of multifold Ca²⁺ mobilizing messengers.The signaling pathway was delineated using different inhibitors and techniques such as platelet aggregation assay, intracellular calcium measurements, immunoprecipitation, immunoblotting, and flow cytometry.

Results: We observed a sequential formation of cADPR and NAADP through CD38 activation by PKC of non-muscle myosin heavy chain IIA (MHCIIA), resulting in phospholipase C (PLC) activation in the thrombin-stimulated platelets. These findings reveal that PKC is fundamental in activating CD38 and elicits a physiological response in the murine platelets.

Conclusion: PKC is involved in many signaling pathways. Specifically, PKC is involved in the internalization of CD38 via MHCIIA in CD38^+/+ wild-type (WT) and CD38^-/- knockout mice (KO). CD38 generates calcium-mobilizing agents that act on specific receptors of the calcium stores. Calcium triggered platelet aggregation while serving as a secondary messenger.

Keywords: CD38; Calcium; NAADP; PKC; Platelets; cADPR.