Direct Interaction of Organic Cation Transporter 3 with CD63: A Mechanism for Regulating Histamine Release in Granulocytes

Аннотация

Granulocytes, particularly basophils and mast cells, play a pivotal role in allergic and inflammatory responses through the rapid release of histamine. The precise mechanisms regulating intracellular histamine levels and its subsequent exocytosis are critical for understanding and modulating these processes. Organic cation transporter 3 (OCT3, SLC22A3) is a polyspecific transporter known to mediate the uptake and efflux of various organic cations, including monoamines like histamine. Tetraspanin CD63 is a transmembrane protein widely used as a marker for granulocyte degranulation and is involved in membrane trafficking and protein complex formation. This study investigates the direct interaction between OCT3 and CD63 and its functional implications for histamine release from granulocytes. Through a combination of molecular, biochemical, and functional assays, we demonstrate that OCT3 co-localizes and physically interacts with CD63 in granulocytes. This interaction appears to influence the subcellular localization and activity of OCT3, thereby modulating intracellular histamine concentrations and subsequent release upon cellular activation. Our findings suggest that CD63 acts as a novel regulator of OCT3 function, providing a mechanistic link between histamine transport and granulocyte degranulation. This discovery sheds light on the intricate regulatory networks governing histamine homeostasis in immune cells and opens new avenues for therapeutic interventions in allergic and inflammatory diseases. Keywords: Organic Cation Transporter 3, CD63, Histamine Release, Granulocytes, Protein–Protein Interaction, Immune Regulation, Mast Cell Degranulation, Allergic Response, Vesicular Trafficking, Inflammatory Mediators. polyspecific membrane proteins that facilitate the Introduction: Allergic reactions and inflammatory transport of a wide range of endogenous and processes are often characterized by the rapid release exogenous organic cations, including of potent mediators, chief among them histamine, neurotransmitters, hormones, and numerous from immune cells such as basophils and mast cells, therapeutic drugs [43, 62]. Among these, Organic collectively referred to as granulocytes [52, 56]. Cation Transporter 3 (OCT3, encoded by SLC22A3) is Histamine, a biogenic amine, exerts its effects through particularly notable for its broad substrate specificity various histamine receptors, contributing to symptoms and its expression in various tissues, including the like vasodilation, increased vascular permeability, and brain, kidney, and immune cells [15, 51, 62]. OCT3 has smooth muscle contraction [37]. The tightly regulated been identified as an extraneuronal monoamine control of intracellular histamine levels is therefore transporter (uptake2) capable of translocating crucial for maintaining physiological homeostasis and monoamine neurotransmitters such as serotonin, preventing pathological immune responses. norepinephrine, and dopamine, as well as histamine Organic cation transporters (OCTs) are a family of [19, 59, 85, 87]. Its role in regulating extracellular International Journal of Medical Sciences And Clinical Research 1 https://theusajournals.com/index.php/ijmscr International Journal of Medical Sciences And Clinical Research (ISSN: 2771-2265) monoamine concentrations, particularly serotonin, has granulocytes. been well-established in the central nervous system [7,