A study on blocking store-operated Ca²⁺ entry in pulmonary arterial smooth muscle cells with xyloketals from marine fungi

Abstract

In this study, the effect of four xyloketals 1-4 on store-operated calcium entry (SOCE) was investigated in primary distal pulmonary arterial smooth muscle cells (PASMCs) isolated from mice. The results showed that xyloketal A (1), an unusual ketal with C-3 symmetry, exhibited strong SOCE blocking activity. Secretion of interleukin-8 (IL-8) was also inhibited by xyloketal A. The parallel artificial membrane permeability assay (PAMPA) of 1-4 suggested that these xyloketals penetrated easily through the cell membrane. Moreover, the molecular docking study of xyloketal A with activation region of the stromal interaction molecule (STIM) 1 and the calcium release-activated calcium modulator (ORAI) 1 (STIM1-ORAI1) protein complex, the key domain of SOCE, revealed that xyloketal A exhibited a noncovalent interaction with the key residue lysine 363 (LYS363) in the identified cytosolic regions in STIM1-C. These findings provided useful information about xyloketal A as a SOCE inhibitor for further evaluation.

T-2 Toxin Exposure Induces Apoptosis in TM3 Cells by Inhibiting Mammalian Target of Rapamycin/Serine/Threonine Protein Kinase(mTORC2/AKT) to Promote Ca2+Production

“…As an important second messenger in cells, Ca 2+ is closely related to a series of important physiological and pathological processes, such as proliferation, differentiation, development, and cell death. The accumulated evidence has demonstrated that when cells are stimulated with T-2 toxin, it leads to the activation of store-operated calcium entry, which plays a crucial role in regulating Ca 2+ signaling and cellular responses in arterial smooth muscle cells [ 30 ]. Notably, Decuypere et al has reported that Ca 2+ is the key player in the canonical mTOR-controlled autophagy pathway [ 31 ].…”

miR-185 silencing promotes the progression of atherosclerosis via targeting stromal interaction molecule 1

“…Meanwhile, STIM1 is the "key" to activate calcium channels on the cell membrane. STIM1 is widespread in nonexcitable cells, including tumor cells and vascular smooth muscle cells (VSMCs) [26][27][28].…”