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. 2014 Jul 31;5:289. doi: 10.3389/fphys.2014.00289

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Copyright © 2014 Lorca, Prabagaran and England.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Several mechanisms modulate the BK_Ca channel in the myometrium. Certain splice variants (SV1 and mK44) of the BK_Ca channel are retained in the endoplasmic reticulum, whereas actin filaments induce traffic of BK_Ca to the plasma membrane of the myometrial smooth muscle cell (MSMC). Localization of BK_Ca channels in membrane microdomains (i.e., caveolae) and interaction with caveolin-1 and -2 and actin filaments modulate the channel's activity. The BK_Ca auxiliary β1- and β2-subunits modify channel activation by direct interaction and, in the case of β1, by inducing its internalization to endosomes. Novel BK_Ca auxiliary γ-subunits are expressed in the uterus, but their significance for MSMC excitability has not been assessed. The vasoactive molecules nitric oxide (NO) and epoxyeicosatrienoic acid (5,6-EET) induce relaxation of the myometrium likely by modulation of BK_Ca channel activity. The steroid hormones 17β-estradiol (E₂) and progesterone (P₄) are important in maintaining pregnancy and inducing labor. These hormones modulate activity of the BK_Ca channel in several ways: directly modulating BK_Ca channel activity, inducing proteosomal degradation of the channel, and regulating expression of the genes encoding the BK_Ca α-subunit (KCNMA1/mSlo1) or β-subunits (KCNMB1 and KCNMB2). Another pregnancy-related hormone, human chorionic gonadotropin (hCG), modulates BK_Ca channel activity to induce relaxation of the myometrium. Several G-protein coupled receptors (GPCRs) regulate BK_Ca channel activity in MSMCs. Norepinephrine (NE) and nociceptin bind their receptors, β2- and β3-adrenoceptors (β2- and β3-AR) and the orphan opioid receptor-like 1 (ORL-1), respectively, and thereby activate G-proteins (Gα_s, Gβγ). This leads to adenylyl cyclase (AC) production of cyclic AMP (cAMP), which activates protein kinase A (PKA) and modulates BK_Ca channel activity. Oxytocin and melatonin stimulate oxytocin receptor (OTR) and melatonin receptors 1 and 2 (MT1 and MT2), respectively, and thereby induce Gα_q/11-dependent activation of phospholipase C (PLC). This leads to production of diacylglycerol (DAG), which in turn causes protein kinase C (PKC)-dependent phosphorylation of the BK_Ca channel. PLC also produces inositol 1,4,5-triphosphate (IP₃) from membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP₂) and thereby brings about Ca²⁺ release from the sarcoplasmic reticulum. In addition to activation by Ca²⁺ release from intracellular stores, the BK_Ca channel is activated by Ca²⁺ influx from nearby voltage- or ligand-gated Ca²⁺ channels (VGCC and LGCC, respectively). Corticotropin-releasing hormone (CRH) binds to its receptors CRH-R1 and CRH-R2, which are linked to multiple signaling pathways and induce up- or down-regulation of BK_Ca channel activity. Finally, a particular BK_Ca channel (mitoBK_Ca) targets to the inner membrane of mitochondria and may influence MSMC contractility.