Relaxin stimulates myometrial calcium-activated potassium channel activity via protein kinase A

Meera, P.; Anwer, Khursheed; Monga, M.; Oberti, Carlos; Stefani, Enrico; Toro, Ligia; Sanborn, Barbara M.

doi:10.1152/ajpcell.1995.269.2.c312

Cited by 75 publications

(57 citation statements)

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“…Relaxin binding to its cognate receptor(s) and postreceptor signalling are likely to be complex and cell-and tissue-specific. Relaxin has been reported to enhance cAMP formation in human endometrial (29) and anterior pituitary cells (30), to inhibit Ca 2 ϩ influx in myometrial cells (31) and mast cells (32), and to induce protein kinase C translocation from cytosol to membranes in endometrial cells (33). Additionally, binding of relaxin to certain cell types is estrogen-dependent while binding to others is not (34), and certain phenotypic alterations are dependent on the presence of both relaxin and estrogen while others are not (17).…”

Section: Discussionmentioning

confidence: 99%

Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

Unemori¹,

Pickford²,

Salles³

et al. 1996

J. Clin. Invest.

321

278

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Pulmonary fibrosis is the common end stage of a number of pneumopathies. In this study, we examined the ability of the human cytokine, relaxin, to block extracellular matrix deposition by human lung fibroblasts in vitro, and to inhibit lung fibrosis in a bleomycin-induced murine model. In vitro, relaxin (1-100 ng/ml) inhibited the transforming growth factor-␤ -mediated over-expression of interstitial collagen types I and III by human lung fibroblasts by up to 45% in a dose-dependent manner. Relaxin did not affect basal levels of collagen expression in the absence of TGF-␤ -induced stimulation. Relaxin also blocked transforming growth factor-␤ -induced upregulation of fibronectin by 80% at the highest relaxin dose tested (100 ng/ml). The expression of matrix metalloproteinase-1, or procollagenase, was stimulated in a biphasic, dose-dependent manner by relaxin. In vivo, relaxin, at a steady state circulating concentration of ‫ف‬ 50 ng/ml, inhibited bleomycin-mediated alveolar thickening compared with the vehicle only control group ( P Ͻ 0.05). Relaxin also restored bleomycin-induced collagen accumulation, as measured by lung hydroxyproline content, to normal levels ( P Ͻ 0.05). In summary, relaxin induced a matrix degradative phenotype in human lung fibroblasts in vitro and inhibited bleomycin-induced fibrosis in a murine model in vivo. These data indicate that relaxin may be efficacious in the treatment of pathologies characterized by lung fibrosis. ( J. Clin. Invest. 1996. 98:2739-2745)

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Section: Discussionmentioning

confidence: 99%

Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

Unemori¹,

Pickford²,

Salles³

et al. 1996

J. Clin. Invest.

321

278

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“…Other mechanisms involving, inter alia, endothelin, NO and relaxin (Goldsmith et al 1995, Dong & Yallampalli 1996 may also regulate myometrial contractility. In the rat, a decline in luteal relaxin production will contribute to increased excitability, removing relaxin's inhibitory actions, mediated by protein kinase A, on myometrial cells (Meera et al 1995); this may involve interference with G q/11 which mediates oxytocin actions . Thus, while oxytocin may play some role in the initiation of labour, there are certainly other uterine mechanisms that can substitute for it in its absence, and which indeed may play a more dominant role.…”

Section: Initiation Of Deliverymentioning

confidence: 99%

Sex, parturition and motherhood without oxytocin?

Ja¹,

Leng²

1998

Journal of Endocrinology

147

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“…The molecular mechanism by which channel modulation occurs is unclear, however, since studies have indicated that single maxi-K channels are regulated by phosphorylation and by phosphorylation-independent G protein interactions (5,6,(11)(12)(13)(14). Further, with respect to channel phosphorylation, maxi-K channel stimulation has been attributed to channel phosphorylation by cAMP-dependent protein kinase (5,6,11,15,16), by cGMP-dependent protein kinase (17)(18)(19)(20)(21), and by channel dephosphorylation (19,22,23). Maxi-K channels are composed of at least two dissimilar subunits: the ␣ subunit, which forms the channel pore (24 -27), and the ␤ subunit (28 -30), which modifies the voltage and calcium sensitivity of the pore-forming subunit (31).…”

mentioning

confidence: 99%

Reconstitution of β-Adrenergic Modulation of Large Conductance, Calcium-activated Potassium (Maxi-K) Channels in Xenopus Oocytes

Nara

Dhulipala

Wang

et al. 1998

Journal of Biological Chemistry

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The human large conductance, calcium-activated potassium (maxi-K) channel (␣ and ␤ subunits) and ␤ 2 -adrenergic receptor genes were coexpressed in Xenopus oocytes in order to study the mechanism of ␤-adrenergic modulation of channel function. Isoproterenol and forskolin increased maxi-K potassium channel currents in voltage-clamped oocytes expressing the receptor and both channel subunits by 33 ؎ 5% and 35 ؎ 8%, respectively, without affecting current activation or inactivation. The percentage of stimulation by isoproterenol and forskolin was not different in oocytes coexpressing the ␣ and ␤ subunits versus those expressing the only the ␣ subunit, suggesting that the ␣ subunit is the target for regulation. The stimulatory effect of isoproterenol was almost completely blocked by intracellular injection of the cyclic AMP dependent protein kinase (cAMP-PK) regulatory subunit, whereas injection of a cyclic GMP dependent protein kinase inhibitory peptide had little effect, indicating that cellular coupling of ␤ 2 -adrenergic receptors to maxi-K channels involves endogenous cAMP-PK. Mutation of one of several potential consensus cAMP-PK phosphorylation sites (serine 869) on the ␣ subunit almost completely inhibited ␤-adrenergic receptor/channel stimulatory coupling, whereas forskolin still stimulated currents moderately (16 ؎ 4%). These data demonstrate that physiological coupling between ␤ 2 receptors and maxi-K channels occurs by the cAMP-PK mediated phosphorylation of serine 869 on the ␣ subunit on the channel.Hormones and neurotransmitters alter cellular excitability in part through the modulation of plasmalemmal ion channel function. Two prominent mechanisms by which hormone/neurotransmitter receptor occupation results in the modulation of membrane ion channels are the phosphorylation of one or more residues of the target channel protein(s) (for review see Ref. 1), and the binding of a heterotrimeric G protein subunit to a modulatory channel domain (for review see Ref.2). Stimulation of ␤ 2 receptors relaxes smooth muscle by modulating the activity of several protein targets (3). One prominent target of ␤ 2 adrenergic signaling in smooth muscle is the large conductance, calcium-activated potassium (maxi-K) 1 channel, the activity of which is markedly increased following receptor binding (4 -7). Modulation of maxi-K channel activity appears to be a functionally important component of ␤-adrenergic relaxation of smooth muscle, since charybdotoxin and iberiotoxin, selective peptide inhibitors of maxi-K channels, markedly inhibit the relaxant ability of isoproterenol and other ␤-adrenergic agents (8 -10). The molecular mechanism by which channel modulation occurs is unclear, however, since studies have indicated that single maxi-K channels are regulated by phosphorylation and by phosphorylation-independent G protein interactions (5,6,(11)(12)(13)(14). Further, with respect to channel phosphorylation, maxi-K channel stimulation has been attributed to channel phosphorylation by cAMP-dependent protein kinase (5,6,11,15,...

show abstract

Relaxin stimulates myometrial calcium-activated potassium channel activity via protein kinase A

Cited by 75 publications

References 0 publications

Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

Sex, parturition and motherhood without oxytocin?

Reconstitution of β-Adrenergic Modulation of Large Conductance, Calcium-activated Potassium (Maxi-K) Channels in Xenopus Oocytes

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