Functional insights into modulation of BKCa channel activity to alter myometrial contractility

Lorca, RamÃ3n A.; Prabagaran, Monali; England, Sarah K.

doi:10.3389/fphys.2014.00289

Cited by 39 publications

(31 citation statements)

References 170 publications

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“…Thereafter the field was open for more modulatory factors from signaling pathways, such as by G-proteins or second messengers, by redox mechanisms, by the action of gasotransmitters, such as nitric oxide (NO), carbon monoxide (CO), or hydrogen sulfide (H 2 S) [ 1 , 44 , 57 , 59 , 86 , 150 ] or more recently by S-acylation (the post-translational attachment of fatty acids to cysteine residues) [ 151 ]. Modulation of ion channels is involved in physiological processes such as transmitter release, hormone secretion or muscle contraction to name just a few [ 11 , 52 , 152 , 153 , 154 , 155 ]. Alterations of channels proteins by oxidative stress and its functional consequences constitutes one further way of channel modulation in a great variety of cells and tissues which will be covered in the following sections.…”

Section: Ion Channels and Oxidative Stressmentioning

confidence: 99%

Oxidative Stress and Maxi Calcium-Activated Potassium (BK) Channels

2015

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All cells contain ion channels in their outer (plasma) and inner (organelle) membranes. Ion channels, similar to other proteins, are targets of oxidative impact, which modulates ion fluxes across membranes. Subsequently, these ion currents affect electrical excitability, such as action potential discharge (in neurons, muscle, and receptor cells), alteration of the membrane resting potential, synaptic transmission, hormone secretion, muscle contraction or coordination of the cell cycle. In this chapter we summarize effects of oxidative stress and redox mechanisms on some ion channels, in particular on maxi calcium-activated potassium (BK) channels which play an outstanding role in a plethora of physiological and pathophysiological functions in almost all cells and tissues. We first elaborate on some general features of ion channel structure and function and then summarize effects of oxidative alterations of ion channels and their functional consequences.

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Section: Ion Channels and Oxidative Stressmentioning

confidence: 99%

Oxidative Stress and Maxi Calcium-Activated Potassium (BK) Channels

2015

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“…BKCa was studied in uterus smooth muscle and was reported that BKCa is over expressed in adenomyosis tissues, and it might cause abnormal muscle contractility that induces the inflammation effects, endometrium impairment and pain [ 13 ]. Moreover, the expression of BKCa in pregnant myometrium is reduced during labor and related with onset of parturition [ 14 , 15 ]. Recently, Li et al [ 16 ] reported the role of BKCa in endometrial cancer HEC-1-B cells.…”

Section: Introductionmentioning

confidence: 99%

BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway

et al. 2018

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BackgroundThe large-conductance, voltage-gated, calcium (Ca (2+))-activated potassium channel (BKCa) plays an important role in regulating Ca (2+) signaling and cell physiological function, and is aberrantly expressed in some types of cancers. The present study focuses on identifying the oncogenic potential and clinical significance of BKCa in endometrial adenocarcinoma, as well as exploring the mechanistic relevance by 17β -estradiol (E2) inducing aberrant activation of MEK1/2 and ERK1/2 via BKCa.MethodsThe expression of BKCa, ERK1/2 and p-ERK1/2 were examined by immunohistochemical staining in 263 cases, including 185 primary types I endometrial cancer tissues, 38 atypical endometrial hyperplasia tissues and 40 normal endometrium tissues. Cell growth, cycle, apoptosis rate, migration and invasion was separately tested in Ishikawa cells using siRNA-BKCa and/or E2 treatment, as well as the expression of these interested proteins by western blot analysis.ResultsWe showed that expression of BKCa is significantly elevated in 185 types I endometrial adenocarcinoma tissues compared to those of the normal endometrium and atypical endometrial hyperplasia tissues. Furthermore, in vitro observations revealed that down-regulation of BKCa expression inhibited cell growth by both enhancing apoptosis and blocking G1/S transition, suppressed cell migration and invasion in Ishakiwa cells, and decreased the expression of p-MEK1/2 and p-ERK1/2. Additionally, RNAi-mediated knockdown of BKCa attenuated the increased cellular growth and invasion, as well as the elevated expression of p-MEK1/2 and p-ERK1/2 proteins, induced by E2 stimulation. More importantly, the aberrant expression of BKCa and p-ERK1/2 were closely related with poor prognostic factors in type I endometrial cancer, and up-regulated expression of p-ERK1/2 was significantly associated with shorter disease-free survival (DFS) and overall survival (OS) and was an independent prognostic factor in type I endometrial cancer patients.ConclusionOur results demonstrated that BKCa and the key downstream effectors p-ERK1/2 could be involved in important signaling pathways in initiation and development of endometrial adenocarcinoma and may provide a new therapeutic approach for women with endometrial cancer.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5027-9) contains supplementary material, which is available to authorized users.

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“…The BK Ca channel is made up of four pore-forming ␣-subunits to which accessory ␤-subunits can attach (51,63). Four classes of ␤-subunits have been identified, although there may be more (62,84). These accessory ␤-subunits can regulate voltage and Ca 2ϩ sensitivity to specialize BK Ca channel-opening behavior, with the ␤ 1 -subunit being the most common ␤-subunit in vascular smooth muscle cells (13,63).…”

Section: Prenatal Chronic Hypoxia and Enos-dependent Relaxationmentioning

confidence: 99%

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Blum-Johnston

Thorpe

Wee

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of largeconductance Ca 2ϩ -activated K ϩ (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca 2ϩ . Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca 2ϩ signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (ϳ140 days gestation) and newborn, 10-to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for Ͼ100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca 2ϩ responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 M nitro-L-arginine methyl ester or 10 M 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel ␣1-subunit expression but increased ␤1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes. potassium channels; sheep; pulmonary artery; contractility; maturation; hypoxia REGULATION OF SMOOTH MUSCLE tone in pulmonary arteries during development is a delicate balance of vasoconstrictive and vasorelaxant pathways. Endothelial cells play a crucial role in determining the overall level of vasorelaxation (39, 67), and endothelium-dependent relaxation is partially mediated through bradykinin stimulation (31). Bradykinin is a potent vasodilator that is important in the fetal pulmonary circulation, as well as during inflammation, and its relationship to pulmonary hypertension has been explored (5, 31, 83).Endothelial bradykinin receptor activation induces vasorelaxation through modulation of several different intracellular signaling pathways that are largely dependent on a rise of endothelial intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (67). The most widely studied pathway is bradykinin-induced activation of endothelial nitric oxide (NO) synthase (eNOS), an enzyme that generates NO (64). NO acts on nearby smooth muscle cells to cause downstream stimulation of soluble guanylate cyclase (sGC) pathways that leads to vasorelaxation (3,45). Previous studies have shown that regulatio...

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Functional insights into modulation of BKCa channel activity to alter myometrial contractility

Cited by 39 publications

References 170 publications

Oxidative Stress and Maxi Calcium-Activated Potassium (BK) Channels

Oxidative Stress and Maxi Calcium-Activated Potassium (BK) Channels

BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

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