Depression of CaV1.2 activation and expression in mast cells ameliorates allergic inflammation diseases.

Abstract

Allergic inflammation is closely related to the activation of mast cells (MCs), which is regulated by its intracellular Ca²⁺ level, but the intake and effects of the intracellular Ca²⁺ remain unclear. The Ca²⁺ influx is controlled by members of Ca²⁺ channels, among which calcium voltage-gated channel subunit alpha1 C (Ca_V1.2) is the most robust. This study aimed to reveal the role and underlying mechanism of MC Ca_V1.2 in allergic inflammation. We found that Ca_V1.2 participated in MC activation and allergic inflammation. Nimodipine (Nim), as a strong Ca_V1.2-specific antagonist, ameliorated allergic inflammation in mice. Further, Ca_V1.2 activation in MC was triggered by phosphatizing at its Ser1928 through protein kinase C (PKC), which calcium/calmodulin-dependent protein kinase II (CaMKII) catalyzed. Overexpression or knockdown of MC Ca_V1.2 influenced MC activation. Importantly, Ca_V1.2 expression in MC had detrimental effects, while its deficiency ameliorated allergic pulmonary inflammation. Results provide novel insights into Ca_V1.2 function and a potential drug target for controlling allergic inflammation.