Guilty by association: direct interaction with the tetraspanin CD63 suggests a role for organic cation transporter 3 in histamine release from granulocytes.

BACKGROUND: The organic cation transporter 3 (OCT3) is a ubiquitous transporter that carries both endogenous and exogenous substrates, such as histamine and cisplatin. Our investigations have shown that OCT3 directly interacts with the tetraspanin CD63. CD63 is a marker for activated basophils and mast cells, which are granulocytes capable of rapidly releasing large amounts of histamine. This makes them key players in the development of allergic reactions. METHODS AND RESULTS: In this work, we demonstrated that OCT3 is present in murine and human basophils and is strongly colocalized with CD63 in a specific region of the plasma membrane, particularly after cell activation leading to histamine release. Furthermore, we confirmed that part of the histamine release from basophils is mediated by OCT3. In a mouse model of contact dermatitis, the presence of OCT3 is crucial for determining the severity of the allergic reaction. The presence of CD63 also seems to be important for regulating the allergic response, although it does not directly affect histamine secretion. RNA-Seq and metabolome analyses revealed that wild-type mice and mice with genetic deletion of OCT3 (OCT3(-/-)) are phenotypically very similar, and that the observed effects in OCT3(-/-) organisms can be attributed mainly to the genetic deletion of the OCT3 transporter. CONCLUSIONS: In conclusion, OCT3 is a transporter for histamine in granulocytes, which plays a crucial role in determining the intensity of allergic reactions and may be a target for interventions aimed at reducing their severity.