Oxytocin mobilizes calcium from a unique heparin-sensitive and thapsigargin-sensitive store in single myometrial cells from pregnant rats

Arnaudeau, Serge; Leprêtre, Nathalie; Mironneau, Jean

doi:10.1007/bf00374751

Cited by 63 publications

(51 citation statements)

References 31 publications

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“…The effect of nifedipine on human myometrial strips was more marked in term not-in-labor than in term-labor specimens [43]. A significant proportion of oxytocin and PGF2α-induced contractions and increases in [Ca 2+ ] i in late pregnant guinea pig myometrium was attributed to Ca 2+ entry inhibited by L-type Ca blockers [44], as was the response in pregnant rat myometrial cell [45]. In contrast, no effect of nifedipine on oxytocin-stimulated increases in [Ca 2+ ] i was observed in nonpregnant human myometrial cells [46], and L-type blockers had no effect on oxytocin-stimulated PI turnover [2,47].…”

Section: Proteins Responsible For Membrane Calcium Entry and Exit Patmentioning

confidence: 91%

“…In other smooth muscles, L-type channels can be stimulated by GPCR pathways involving Gβγ, PI-3K and PKC [50]. Oxytocin has been implicated in the opening of other cation channels (consistent with SRCE) and of Ca 2+ -activated Cl − channels in myometrium, leading indirectly to depolarization and opening of voltage-dependent Ca 2+ channels [51].…”

Section: Proteins Responsible For Membrane Calcium Entry and Exit Patmentioning

confidence: 99%

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Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics

Sanborn

2007

Seminars in Cell & Developmental Biology

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Understanding the basis for the control of myometrial contractant and relaxant signaling pathways is important to understanding how to manage myometrial contractions. Signaling pathways are influenced by the level of expression of the signals and signal pathway components, the location of these components in the appropriate subcellular environment, and covalent modification. Crosstalk between these pathways regulates the effectiveness of signal transduction and represents an important way by which hormones can regulate phenotype. This review deals primarily with signaling pathways that control Ca 2+ entry and intracellular release, as well as the interplay between these pathways.

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Section: Proteins Responsible For Membrane Calcium Entry and Exit Patmentioning

confidence: 91%

Section: Proteins Responsible For Membrane Calcium Entry and Exit Patmentioning

confidence: 99%

Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics

Sanborn

2007

Seminars in Cell & Developmental Biology

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“…Oxytocin-stimulated GTPase and PLC activities can be attenuated by preincubation of myometrial membrane preparations with an antibody directed against the C terminus of G␣ q/11 (5). These data, together with results from microinjection experiments (6), indicate that OTR couples functionally to G␣ q . In addition, OTR has been reported to couple to G␣ i (7) and G␣ h (8).…”

Section: : 814-823 2002)mentioning

confidence: 65%

Lysine 270 in the Third Intracellular Domain of the Oxytocin Receptor is an Important Determinant for Gα_qCoupling Specificity

Yang¹,

Wang²,

Zhong³

et al. 2002

Molecular Endocrinology

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To identify structural elements important to specific G␣ q coupling in the oxytocin receptor (OTR), intracellular domains were exchanged between OTR and G␣ s -coupled vasopressin V 2 receptors (V 2 Rs). Substitution of sequence from the second (2i) and third (3i) intracellular domains of V 2 R into comparable positions in OTR markedly reduced ligand affinity and resulted in a loss of G␣ q coupling. Substitution of the 2i domain of OTR into V 2 R decreased ligand affinity and vasopressin-stimulated adenylyl cyclase activity and only slightly increased phosphatidylinositide turnover. In contrast, substitution of the OTR3i domain into V 2 R produced a receptor chimera with high ligand affinity, decreased vasopressin-stimulated adenylyl cyclase activity, and markedly enhanced ligandstimulated phosphatidylinositide turnover. The Cterminal 36 amino acids, but not the N-terminal 13 amino acids, of the OTR3i domain contained the determinants critical for enhanced activation of PLC. Mutation of a single lysine in the C-terminal OTR3i sequence to the corresponding V 2 R residue (valine) eliminated the enhanced ability of the V 2 R chimera to stimulate PLC but did not affect maximal adenylyl cyclase stimulation. Furthermore, mutation of this residue (K270) in wild-type OTR completely abolished the ability of the receptor to stimulate phosphatidylinositide turnover, with only a small reduction in ligand affinity. These data demonstrate that OTR K270 is critically important in the stimulation by OTR of phosphatidylinositide turnover and that this determinant can also increase this activity in the V 2 R chimera. Mutation of K270 also adversely affects the ability of OTR to stimulate ERK1/2 phosphorylation. Therefore, this residue plays an important role in the specificity of OTR/G␣ q /PLC coupling. (1-3). The derived amino acid sequence for the oxytocin receptor (OTR) places it in the class I GPCR family (2, 4). Interaction of OTR with its ligand and with target G proteins is key to oxytocin-stimulated signaling in the myometrial smooth muscle of the uterus. Oxytocin-stimulated GTPase and PLC activities can be attenuated by preincubation of myometrial membrane preparations with an antibody directed against the C terminus of G␣ q/11 (5). These data, together with results from microinjection experiments (6), indicate that OTR couples functionally to G␣ q . In addition, OTR has been reported to couple to G␣ i (7) and G␣ h (8).Random and site-directed mutagenesis, substitution of putative interaction sites in receptor chimeras, and interference assays have implicated the second (2i), third (3i), and fourth (4i) intracellular domains of GPCRs in mediating the specificity and efficacy of coupling to G proteins (1-3). N-and C-terminal regions of GPCR 3i domains appear particularly important for defining G protein specificity in some GPCRs. However, although there is recognizable sequence homology in a given receptor subgroup, there is often a minimum of conservation of specific residues in these regions between receptor subgroups c...

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“…Several human and rat myometrium studies (2,7,16) concluded on the absence of RYR function in Ca 2ϩ signals. In smooth muscles, the functions of RYRs are principally to encode Ca 2ϩ sparks and Ca 2ϩ waves to regulate contraction (21).…”

Section: Discussionmentioning

confidence: 99%

“…RYRs were then suggested to be involved in a Ca 2ϩ -induced Ca 2ϩ release mechanism in pregnant but not nonpregnant myometrium (39). However, in physiological solution, caffeine cannot activate RYRs in freshly isolated myocytes from the rat pregnant myometrium (2), although some responses were observed in cultured cells (24). In the mouse myometrium, the RYR3 subtype has been shown to be activated by caffeine only when the SR is Ca 2ϩ overloaded (28).…”

Section: Intracellular Camentioning

confidence: 99%

Role of RYR3 splice variants in calcium signaling in mouse nonpregnant and pregnant myometrium

Dabertrand¹,

Fritz²,

Mironneau³

et al. 2007

American Journal of Physiology-Cell Physiology

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Alternative splicing of ryanodine receptor subtype 3 (RYR3) may generate a short isoform (RYR3S) without channel function and a functional full-length isoform (RYR3L). The RYR3S isoform has been shown to negatively regulate the native RYR2 subtype in smooth muscle cells as well as the RYR3L isoform when both isoforms were coexpressed in HEK-293 cells. Mouse myometrium expresses only the RYR3 subtype, but the role of RYR3 isoforms obtained by alternative splicing and their activation by cADP-ribose during pregnancy have never been investigated. Here, we show that both RYR3S and RYR3L isoforms are differentially expressed in nonpregnant and pregnant mouse myometrium. The use of antisense oligonucleotides directed against each isoform indicated that only RYR3L was activated by caffeine and cADP-ribose in nonpregnant myometrium. These RYR3L-mediated Ca 2ϩ releases were negatively regulated by RYR3S expression. At the end of pregnancy, the relative expression of RYR3L versus RYR3S and its ability to respond to cADP-ribose were increased. Therefore, our results suggest that physiological regulation of RYR3 alternative splicing may play an essential role at the end of pregnancy. (4,5). Although the activation of InsP 3 Rs is well documented in the myometrium (22,32,35,37), the activation and function of RYRs in the myometrium during pregnancy are still under debate.Three subtypes of RYRs are encoded by three distinct genes [RYR1, RYR2, and RYR3 (for a review, see Ref. 13)], and the expression of RYRs in the myometrium at different stages of pregnancy has been explored (20). The expression of RYR3 has been reported in human, rat, and mouse nonpregnant myometrium and during pregnancy (23, 24, 28), whereas a very low level of RYR2 expression has been found in the pregnant myometrium, but only in the rat (24). RYRs were then suggested to be involved in a Ca 2ϩ -induced Ca 2ϩ release mechanism in pregnant but not nonpregnant myometrium (39). However, in physiological solution, caffeine cannot activate RYRs in freshly isolated myocytes from the rat pregnant myometrium (2), although some responses were observed in cultured cells (24). In the mouse myometrium, the RYR3 subtype has been shown to be activated by caffeine only when the SR is Ca 2ϩ overloaded (28). Several studies about RYR3 in other cell types have indicated that RYR3 is not able to induce an excitation-contraction mechanism (12) but can encode spontaneous Ca 2ϩ release when overexpressed in HEK-293 cells (1, 34). However, several isoforms of RYR3 are expressed by alternative splicing (17,25,29). The short-length isoform (RYR3S) has been described to inhibit RYR2 (9, 17), and the full-length isoform (RYR3L) can form a functional channel in a heterologous system (17). In these studies, it was indicated that both isoforms of RYR3 are potentially expressed in the rabbit and mouse myometrium (9, 17). RYR3S is characterized by the alternative splicing of a 87-bp exon potentially encoding a putative transmembrane domain of the channel (17). Moreover, the RYR3 subtype ...

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Oxytocin mobilizes calcium from a unique heparin-sensitive and thapsigargin-sensitive store in single myometrial cells from pregnant rats

Cited by 63 publications

References 31 publications

Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics

Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics

Lysine 270 in the Third Intracellular Domain of the Oxytocin Receptor is an Important Determinant for Gα_qCoupling Specificity

Role of RYR3 splice variants in calcium signaling in mouse nonpregnant and pregnant myometrium

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Oxytocin mobilizes calcium from a unique heparin-sensitive and thapsigargin-sensitive store in single myometrial cells from pregnant rats

Cited by 63 publications

References 31 publications

Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics

Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics

Lysine 270 in the Third Intracellular Domain of the Oxytocin Receptor is an Important Determinant for GαqCoupling Specificity

Role of RYR3 splice variants in calcium signaling in mouse nonpregnant and pregnant myometrium

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Lysine 270 in the Third Intracellular Domain of the Oxytocin Receptor is an Important Determinant for Gα_qCoupling Specificity