Estrogen increases the expression of BKCa and impairs the contraction of colon smooth muscle via upregulation of sphingosine kinase 1

Abstract Estrogen (E2) may impair the contraction of colonic smooth muscle (SM) leading to constipation. Large conductance Ca 2+ ‐activated K + channels (BK Ca ) are widely expressed in the smooth muscle cells (SMCs) contributing to hyperpolarization and relaxation of SMCs. Sphingosine kinase 1 (SphK1) is known to influence the expression of BK Ca . We aimed to elucidate the potential underlying molecular mechanism of BK Ca and SphK1 that may influence E2‐induced colonic dysmotility. In ovariectomized rats, SM contraction and expression of BK Ca , SphK1, sphingosine‐1‐phosphate receptor (S1PR) were analyzed after the treatment with vehicle, BSA‐E2, E2, and E2 receptor antagonist. The role of BK Ca , SphK1, and S1PR in E2‐induced SM dysmotility was investigated in rat colonic SMCs. The effect of SphK1 on SM contraction as well as on the expression of BK Ca and S1PR was analyzed in SphK1 knock‐out mutant mice and wild‐type (WT) mice treated with or without E2. The E2‐treated group exhibited a weak contraction of colonic SM and a delayed colonic transit. The treatment with E2 significantly upregulated the expression of BK Ca , SphK1, S1PR1, and S1PR2, but not S1PR3, in colon SM and SMCs. Inhibition of BK Ca , SphK1, S1PR1, and S1PR2 expression attenuated the effect of E2 on Ca 2+ mobilization in rat colon SMCs. WT mice treated with E2 showed impaired gastrointestinal motility and enhanced expression of BK Ca , S1PR1, and S1PR2 compared with those without E2 treatment. Conversely, in SphK1 knock‐out mice treated with E2, these effects were partially reversed. E2 increased the release of S1P which in turn could have activated S1PR1 and S1PR2. Loss of SphK1 attenuated the effect of E2 on the upregulation of S1PR1 and S1PR2 expression. These findings indicated that E2 impaired the contraction of colon SM through activation of BK Ca via the upregulation of SphK1 and the release of S1P. In the E2‐induced BK Ca upregulation, S1PR1 and S1PR2 might also be involved. These results may provide further insights into a therapeutic target and optional treatment approaches for patients with constipation.