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• W2068657810 abstract "Expression and regulation of myometrial adenylyl cyclases (AC) were studied during pregnancy. Hybridization of poly(A)+ RNA with specific cDNA probes for enzyme types I–IX indicated 1) the presence of transcripts encoding types II–VI and type IX in rat and human, and type VII in rat and 2) the absence of detectable mRNA for types I and VIII in both species. No substantial change was observed in the amount of specific mRNA and basal AC activity from mid-pregnancy to term. However, activation of the α2-adrenergic receptor/Gi protein pathway resulted in potentiation of Gs-stimulated AC activity at mid-pregnancy but not at term (Mhaouty, S., Cohen-Tannoudji, J., Bouet-Alard, R., Limon-Boulez, I., Maltier, J. P., and Legrand, C. (1995) J. Biol. Chem. 270, 11012–11016). We demonstrate in the present work that βγ scavengers transducin-α and QEHA peptide abolished this positive input. On the other hand, increasing submicromolar concentrations of free Ca2+, a situation that mimics late term, reduced the forskolin-stimulated AC activity with an IC50 of 3.9 μm. Thus, the presence in myometrium of AC II family (types II, IV, VII) confers ability to G inhibitory proteins to stimulate enzyme activity via βγ complexes at mid-pregnancy, whereas expression of AC III, V, and VI isoforms confers to the myometrial AC system a high sensitivity to inhibition by Ca2+-dependent processes at term. These data suggest that in the pregnant myometrium, the expression of different species of AC with distinct regulatory properties provides a mechanism for integrating positively or negatively the responses to various hormonal inputs existing either during pregnancy or in late term. Expression and regulation of myometrial adenylyl cyclases (AC) were studied during pregnancy. Hybridization of poly(A)+ RNA with specific cDNA probes for enzyme types I–IX indicated 1) the presence of transcripts encoding types II–VI and type IX in rat and human, and type VII in rat and 2) the absence of detectable mRNA for types I and VIII in both species. No substantial change was observed in the amount of specific mRNA and basal AC activity from mid-pregnancy to term. However, activation of the α2-adrenergic receptor/Gi protein pathway resulted in potentiation of Gs-stimulated AC activity at mid-pregnancy but not at term (Mhaouty, S., Cohen-Tannoudji, J., Bouet-Alard, R., Limon-Boulez, I., Maltier, J. P., and Legrand, C. (1995) J. Biol. Chem. 270, 11012–11016). We demonstrate in the present work that βγ scavengers transducin-α and QEHA peptide abolished this positive input. On the other hand, increasing submicromolar concentrations of free Ca2+, a situation that mimics late term, reduced the forskolin-stimulated AC activity with an IC50 of 3.9 μm. Thus, the presence in myometrium of AC II family (types II, IV, VII) confers ability to G inhibitory proteins to stimulate enzyme activity via βγ complexes at mid-pregnancy, whereas expression of AC III, V, and VI isoforms confers to the myometrial AC system a high sensitivity to inhibition by Ca2+-dependent processes at term. These data suggest that in the pregnant myometrium, the expression of different species of AC with distinct regulatory properties provides a mechanism for integrating positively or negatively the responses to various hormonal inputs existing either during pregnancy or in late term. Data on hormonal regulation of myometrial contractility during the course of pregnancy implicate adenylyl cyclase (AC) 1The abbreviations used are: AC, adenylyl cyclases; AR, α2-adrenergic receptor; Gpp(NH)p, guanosine 5′-(β,γ-imido)triphosphate; kb, kilobases; GDPβS, guanyl-5′-yl thiophosphate. 1The abbreviations used are: AC, adenylyl cyclases; AR, α2-adrenergic receptor; Gpp(NH)p, guanosine 5′-(β,γ-imido)triphosphate; kb, kilobases; GDPβS, guanyl-5′-yl thiophosphate. stimulatory pathways as a key component that may affect the degree of intracellular cAMP generation and consequently the contractile state of the uterus. Because one of the major sites of control of the biochemical events leading to uterine relaxation during normal pregnancy lies at the AC/cAMP system, the identification of AC isoforms in the pregnant myometrium is essential in understanding the influence exerted by the regulatory external signals (neurotransmitters and hormones) acting via G protein-coupled receptors. Hormonal control of AC activity is brought about by receptor-catalyzed activation of heterotrimeric G proteins that in turn regulate the cyclases by the release of α or βγ subunits or kinase activation. Recent studies have revealed an unexpected diversity of G protein-regulated AC by identifying nine distinct AC cDNA from various mammalian tissues (1Krupinski J. Coussen F. Bakalyar H.A. Tang W.J. Feinstein P.G. Orth K. Slaughter C. Reed R.R. Gilman A.G. Science. 1989; 244: 1558-1564Crossref PubMed Scopus (505) Google Scholar, 2Yoshimura M. Cooper D.M.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 6716-6720Crossref PubMed Scopus (201) Google Scholar, 3Iyengar R. FASEB J. 1993; 7: 768-775Crossref PubMed Scopus (265) Google Scholar, 4Taussig R. Tang W.J. Hepler J.R. Gilman A.G. J. Biol. Chem. 1994; 269: 6093-6100Abstract Full Text PDF PubMed Google Scholar, 5Premont R.T. Matsuoka I. Mattei M.-G. Pouille Y. Defer N. Hanoune J. J. Biol. Chem. 1996; 271: 13900-13907Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). All of these isoforms of AC differ in their tissue distribution and their regulatory properties, providing a mode for different cells to respond diversely to similar external stimuli. Among all of the AC identified so far, the highly similar types II, IV, and VII form the largest known subfamily. Types II and IV share the property of being highly stimulated by βγ subunits of Gi/Goinhibitory proteins in the presence of activated Gsα (6Tang W.J. Gilman A.G. Science. 1991; 254: 1500-1503Crossref PubMed Scopus (741) Google Scholar,7Gao B. Gilman A.G. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 10178-10182Crossref PubMed Scopus (274) Google Scholar). These AC are also influenced by phosphorylation with protein kinase C (8Lustig K.D. Conklin B.R. Herzmark P. Taussig R. Bourne H.R. J. Biol. Chem. 1993; 268: 13900-13905Abstract Full Text PDF PubMed Google Scholar, 9Jacobowitz O. Chen J. Premont R.T. Iyengar R. J. Biol. Chem. 1993; 268: 3829-3832Abstract Full Text PDF PubMed Google Scholar, 10Zimmerman G. Taussig R. J. Biol. Chem. 1996; 271: 27161-27166Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 11Marjamaki A. Sato M. Bouet-Alard R. Yang Q. Limon-Boulez I. Legrand C. Lanier S.M. J. Biol. Chem. 1997; 272: 16466-16473Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). Types V and VI AC, a two-member subfamily, are inhibited directly by low levels of Ca2+ (2Yoshimura M. Cooper D.M.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 6716-6720Crossref PubMed Scopus (201) Google Scholar, 12Premont R.T. Chen J. Ma H.W. Ponnapali M. Iyengar R. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9809-9813Crossref PubMed Scopus (168) Google Scholar), whereas AC I and VIII are regulated positively by Ca2+-calmodulin (13Tang W.J. Krupinski J. Gilman A.G. J. Biol. Chem. 1991; 266: 8595-8603Abstract Full Text PDF PubMed Google Scholar, 14Cali J.J. Zwaagstra J.C. Mons N. Cooper D.M.F. Krupinski J. J. Biol. Chem. 1994; 269: 12190-12195Abstract Full Text PDF PubMed Google Scholar). On the other hand, AC III can be phosphorylated by a calmodulin-dependent protein kinase II in response to the elevation of intracellular Ca2+ which results, in vivo, in a 50% inhibition of hormone-stimulated enzyme (15Wei J. Wayman G. Storm D.R. J. Biol. Chem. 1996; 271: 24231-24235Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). The novel ninth AC is quite distinct from all of the other known AC subfamilies, and it is not affected by G βγ proteins or Ca2+ (5Premont R.T. Matsuoka I. Mattei M.-G. Pouille Y. Defer N. Hanoune J. J. Biol. Chem. 1996; 271: 13900-13907Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Thus, in vivo, when a cell type or tissue expresses various isoforms of AC one may expect that different physiological situations trigger different responses to the same external stimuli depending not only on the type of the receptor and G protein involved but also on the type of adenylyl cyclase to which they are coupled.As an initial approach to this issue in human and rat myometrium, we first characterized the type(s) of AC involved in myometrial signaling in both species during pregnancy. Then, because AC types II and IV are present in human and rat myometria, we examined the possibility that the positive input to the myometrial AC system emanating from the activated α2-adrenergic receptor (AR) coupled to Gi2/Gi3 proteins as described previously (16Mhaouty S. Cohen-Tannoudji J. Bouet-Alard R. Limon-Boulez I. Maltier J.-P. Legrand C. J. Biol. Chem. 1995; 270: 11012-11016Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar) involves Giβγ. This was performed by using transducin-α (17Weiland T. Ronzani M. Jakobs K.H. J. Biol. Chem. 1992; 267: 20791-20797Abstract Full Text PDF PubMed Google Scholar) or a synthetic peptide corresponding to the binding site of βγ in the AC II (18Chen J. Devivo M. Dingus J. Harry A. Li J. Sui J. Carty D.J. Blank J.L. Exton J.H. Stoffel R.H. Inglese J. Lefkowitz R.J. Logothetis D.E. Hildebrandt J.D. Iyengar R. Science. 1995; 268: 1166-1169Crossref PubMed Scopus (235) Google Scholar, 19Weng G. Li J. Dingus J. Hildebrandt J.D. Weinstein H. Iyengar R. J. Biol. Chem. 1996; 271: 26445-26448Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar) which tie up the Giβγ released by α2-AR activation. Finally, because AC types V and VI are also strongly expressed in pregnant myometria, we investigated whether submicromolar concentrations of Ca2+ attenuate forskolin-stimulated AC activity. Elevation of intracellular Ca2+ is precisely the situation that occurs in response to external stimuli in the pregnant myometrium at the time of delivery. Data reported here provide an explanation for the switch in the stimulatory versusinhibitory input to myometrial AC reported at mid-pregnancy or term.DISCUSSIONThis study reports for the first time that pregnant human and rat myometria express transcripts encoding distinct populations of AC. Indeed, using Northern blot analysis, we detected AC II–VI and IX in both human and rat myometria, whereas type VII was present only in rat. The absence of detectable levels of types I and VIII mRNA is consistent with previous findings showing that these two enzymes are brain-specific. Although it is generally considered that all the structures that expressed more than one AC type contain several cell types, it is important to note that in the myometrium, smooth muscle cells present a great abundance and are distributed evenly throughout the longitudinal and circular layers. Only few other cell types (vascular or conjunctive) are observed. AC mRNA detected in this study using in situ hybridization derived mainly from myometrial cells as exemplified in Fig.6, A and B, illustrating the specific expression of AC type II in smooth muscle cells. Furthermore, in agreement with previous results (29Furuyama T. Inagaki S. Takagi H. Mol. Brain Res. 1993; 19: 165-170Crossref PubMed Scopus (35) Google Scholar, 33Mons N. Yoshimura M. Cooper D.M.F. Synapse. 1993; 14: 51-59Crossref PubMed Scopus (82) Google Scholar), control slides of rat brain hybridized in the same conditions indicated a strong expression of AC II in pyramidal cells and dentate gyrus of hippocampus (Fig. 6 C). All of these observations suggested to us that Gβγ-activated (types II and IV and presumably VII) and Ca2+-inhibitable (types III, V, and VI) AC expressed in human and rat myometrium might contribute to physiological processes sensitive to Gi proteins and Ca2+-dependent regulation of the cAMP generation in this tissue.To estimate the total levels of AC in myometria from mid-pregnant and delivering rats, we measured the maximal levels of high affinity [3H]forskolin binding sites (B max). In the presence of Gpp(NH)p, our results demonstrated an increase of the [3H]forskolin binding sites at mid-pregnancy but not at term. Because it was proposed that the guanine nucleotide-stimulated high affinity binding of [3H]forskolin represents binding to the Gs-activated form of AC, one may suggest that the Gs/catalytic unit complexes are reduced at term. Potential differences in the affinity of this ligand (K d ) observed in mid-pregnant rat myometrium could mean either differences in the interaction of [3H]forskolin with some isoforms of AC present in the myometrium or differential expression of isoforms according to the stage of pregnancy. Although our results show that the expression of AC transcripts in rat myometrium over the second half of pregnancy remains stable, we cannot exclude possible changes at the protein levels. At the present time, this issue cannot be settled because no specific antibody that allows to quantify directly each AC type is available. Interestingly, the decrease of [3H]forskolin binding sites number reported at term in the presence of Gpp(NH)p correlates well with the decline of forskolin-stimulated AC activity. Furthermore, the reduced ability of guanine nucleotides or cholera toxin (acting at the Gs level) to stimulate myometrial AC activity at term and the fact that Mn2+/GDPβS (acting solely at the catalytic unit of the AC, 34Strittmatter S. Neer E.J. Proc. Natl. Acad. Sci. U. S. A. 1980; 77: 6344-6348Crossref PubMed Scopus (75) Google Scholar) has no different regulatory effects, points to a defect in the availability or functionality of regulatory Gs proteins rather than a reduction in the catalytic subunits of AC. This conclusion supports previous data of our laboratory establishing that amounts of cholera toxin-catalyzed ADP-ribosylated Gsα subunits diminished by 3-fold at delivery versus pregnancy (35Elwardy-Mérézak J. Maltier J.P. Cohen-Tannoudji J. Lécrivain J.L. Vivat V. Legrand C. J. Mol. Endocrinol. 1994; 13: 23-37Crossref PubMed Scopus (35) Google Scholar). In addition, as shown by radioligand binding experiments, the reduced response to isoproterenol at term is not caused by changes in total β-AR number (28Vivat V. Cohen-Tannoudji J. Revelli J.P. Muzzin P. Giacobino J.P. Maltier J.P. Legrand C. J. Biol. Chem. 1992; 267: 7975-7978Abstract Full Text PDF PubMed Google Scholar) but is the consequence of Gs protein uncoupling (24Cohen-Tannoudji J. Vivat V. Heilmann J. Legrand C. Maltier J.P. J. Mol. Endocrinol. 1991; 6: 137-145Crossref PubMed Scopus (39) Google Scholar).Previously, we have shown that catecholamines acting through α2-AR/Gi2–3 proteins signaling pathway potentiate β-AR-stimulated AC activity in rat myometrium at mid-pregnancy (16Mhaouty S. Cohen-Tannoudji J. Bouet-Alard R. Limon-Boulez I. Maltier J.-P. Legrand C. J. Biol. Chem. 1995; 270: 11012-11016Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). These data suggested a tight interplay between the two adrenergic pathways in the regulation of AC types II and IV through βγ complexes according to the findings of Tang and Gilman (6Tang W.J. Gilman A.G. Science. 1991; 254: 1500-1503Crossref PubMed Scopus (741) Google Scholar), Gao and Gilman (7Gao B. Gilman A.G. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 10178-10182Crossref PubMed Scopus (274) Google Scholar), and Federman et al. (36Federman A.D. Conklin B.R. Schrader K.A. Reed R.R. Bourne H.R. Nature. 1992; 356: 159-161Crossref PubMed Scopus (480) Google Scholar). Here, the demonstration that the positive input emanating from the activated α2-AR involves βγ complexes of Giproteins expressed in rat myometrium (37Cohen-Tannoudji J. Mhaouty S. Elwardy-Mérézak J. Lécrivain J.L. Robin M.T. Legrand C. Maltier J.P. Biol. Reprod. 1995; 53: 55-64Crossref PubMed Scopus (48) Google Scholar) was achieved using transducin-α and QEHA peptide: both factors abolished the potentiation of AC activity induced by the α2-AR agonist clonidine. In the same work (16Mhaouty S. Cohen-Tannoudji J. Bouet-Alard R. Limon-Boulez I. Maltier J.-P. Legrand C. J. Biol. Chem. 1995; 270: 11012-11016Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar), we reported a switch in the stimulatory versus inhibitory input to AC population from the α2-AR/Gi protein-signaling pathway at late term. The idea that changes in AC isoform expression might underlie such a versatility of the α2-AR signal is highly speculative inasmuch as it is not possible to demonstrate that some AC types (specially types II and IV) are the most prevalent isoforms in the mid-pregnant myometrium compared with late term myometrium. At this latter period, no substantial modification in the amounts of specific types of AC transcripts as well as no alteration in the basal activity of the AC system have been observed. So, in the parturient rat myometrium, when the balance among Gi3, Gi2, and Gs proteins was changed (35Elwardy-Mérézak J. Maltier J.P. Cohen-Tannoudji J. Lécrivain J.L. Vivat V. Legrand C. J. Mol. Endocrinol. 1994; 13: 23-37Crossref PubMed Scopus (35) Google Scholar, 37Cohen-Tannoudji J. Mhaouty S. Elwardy-Mérézak J. Lécrivain J.L. Robin M.T. Legrand C. Maltier J.P. Biol. Reprod. 1995; 53: 55-64Crossref PubMed Scopus (48) Google Scholar) we suggest the possibility that distinct patterns of responsiveness of the myometrial AC population may account for the switch between the two types of input (positive and negative) initiated by α2-AR activation. Interestingly, a decline of immunodetected β subunits of G proteins which is expected to reflect the status of the βγ complexes (38Tanfin Z. Goureau O. Milligan G. Harbon S. FEBS Lett. 1991; 278: 4-8Crossref PubMed Scopus (34) Google Scholar) paralleled the 1.7-fold decrease of Gi3α subunit in the late pregnant rat myometrium (37Cohen-Tannoudji J. Mhaouty S. Elwardy-Mérézak J. Lécrivain J.L. Robin M.T. Legrand C. Maltier J.P. Biol. Reprod. 1995; 53: 55-64Crossref PubMed Scopus (48) Google Scholar, 38Tanfin Z. Goureau O. Milligan G. Harbon S. FEBS Lett. 1991; 278: 4-8Crossref PubMed Scopus (34) Google Scholar). It is then conceivable to propose that the reduced availability of Giβγ complexes together with the reduced levels of functional Gsα protein may underlie the loss of AC potentiation observed at term in response to β2-/α2-AR activation. On the other hand, the role of Gi protein-coupled α2-AR in mediating AC inhibition in the late pregnant myometrium has been well documented in rat (16Mhaouty S. Cohen-Tannoudji J. Bouet-Alard R. Limon-Boulez I. Maltier J.-P. Legrand C. J. Biol. Chem. 1995; 270: 11012-11016Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar) and human (39Breuiller M. Rouot B. Litime M.H. Leroy J. Ferré F. J. Clin. Endocrinol. Metab. 1990; 70: 1299-1304Crossref PubMed Scopus (22) Google Scholar). To date, the inhibitory regulation of AC type II through Gi proteins still remains controversial since the data reported by Chen and Iyengar in COS7 cells transfectants (40Chen J. Iyengar R. J. Biol. Chem. 1993; 268: 12253-12256Abstract Full Text PDF PubMed Google Scholar) and the recent work of Lanier's laboratory in collaboration with us on DDT1-MF2 cells AC II transfectants (11Marjamaki A. Sato M. Bouet-Alard R. Yang Q. Limon-Boulez I. Legrand C. Lanier S.M. J. Biol. Chem. 1997; 272: 16466-16473Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar) are not in agreement with other findings in Sf9 cell membranes (4Taussig R. Tang W.J. Hepler J.R. Gilman A.G. J. Biol. Chem. 1994; 269: 6093-6100Abstract Full Text PDF PubMed Google Scholar). Nevertheless, AC types III, V, and VI expressed in rat and human myometrium are highly sensitive to inhibition by Giproteins (4Taussig R. Tang W.J. Hepler J.R. Gilman A.G. J. Biol. Chem. 1994; 269: 6093-6100Abstract Full Text PDF PubMed Google Scholar, 40Chen J. Iyengar R. J. Biol. Chem. 1993; 268: 12253-12256Abstract Full Text PDF PubMed Google Scholar) and could then present possible targets to α2-AR/Gi protein-mediated inhibition at term. The presence of AC types V and VI is also consistent with the observation that physiological relevant concentrations of Ca2+ inhibit basal and stimulated AC population in pregnant myometrial membranes of rat (our present work) and human (41Doualla-Bell Koto Maka F. Breuiller M. Leroy M.J. Josserand S. Ferré F. Gynecol. Obstet. Invest. 1990; 30: 169-173Crossref PubMed Scopus (7) Google Scholar). This is in line with preliminary evidences showing that these enzymes are regulated directly by submicromolar concentrations of Ca2+(2Yoshimura M. Cooper D.M.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 6716-6720Crossref PubMed Scopus (201) Google Scholar, 31Cooper D.M.F. Mons N. Fagan K. Cell. Signalling. 1994; 6: 823-840Crossref PubMed Scopus (61) Google Scholar, 32Debernardi M.A. Munshi R. Yoshimura M. Cooper D.M.F. Brooker G. Biochem. J. 1993; 293: 325-328Crossref PubMed Scopus (41) Google Scholar). As demonstrated for cardiac adenylyl cyclases (42Colvin R.A. Oibo J.A. Allen R.A. Cell Calcium. 1991; 12: 19-27Crossref PubMed Scopus (49) Google Scholar), the inability of maximally stimulating concentrations of Mg2+to overcome Ca2+ inhibition (data not shown) indicates that Ca2+ concentrations in the μm range are not competitive with Mg2+ (i.e. high affinity effect) by contrast with millimolar concentrations of Ca2+(43Lasker R.D. Downs R.W. Aurbach G.D. Arch. Biochem. Biophys. 1982; 216: 345-355Crossref PubMed Scopus (20) Google Scholar). Half-maximal inhibition value reported in this work is also in agreement with values found for cardiac muscle (42Colvin R.A. Oibo J.A. Allen R.A. Cell Calcium. 1991; 12: 19-27Crossref PubMed Scopus (49) Google Scholar, 44Espinasse I. Iourgenko V. Defer N. Samson F. Hanoune J. Mercadier J.J. J. Mol. Cell. Cardiol. 1995; 27: 1789-1795Abstract Full Text PDF PubMed Scopus (76) Google Scholar) or the aorta smooth muscle (45Piascik M.T. Addison B. Babich M. Arch. Biochem. Biophys. 1995; 241: 28-35Crossref Scopus (9) Google Scholar) AC system. Interestingly, these Ca2+concentrations at which AC inhibition is reported are in the range of those required to activate myosin light chain phosphorylation (46Taylor D.A. Stull J.T. J. Biol. Chem. 1988; 263: 14456-14462Abstract Full Text PDF PubMed Google Scholar) and correspond also to Ca2+ concentrations measured in myometrial membranes from rats close to term treated with the uterotonic agent oxytocin (47Magocsi M. Penniston J. Biochim. Biophys. Acta. 1991; 1063: 7-14Crossref PubMed Scopus (24) Google Scholar). In addition, Ca2+ can affect also indirectly AC activity because inhibition of AC type III activity through its phosphorylation by calmodulin-casein kinase II is mediated by intracellular increase of Ca2+ (15Wei J. Wayman G. Storm D.R. J. Biol. Chem. 1996; 271: 24231-24235Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). In conditions prevailing in vivo in the pregnant myometrium at term when intramyometrial submicromolar concentrations of Ca2+ rise, such regulation may also provide a mechanism for attenuation of hormone-stimulated cAMP generation. Alternatively, Lanier's group together with our laboratory (11Marjamaki A. Sato M. Bouet-Alard R. Yang Q. Limon-Boulez I. Legrand C. Lanier S.M. J. Biol. Chem. 1997; 272: 16466-16473Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar) have established that the stimulatory/inhibitory input to the AC types II and IV initiated through α2-AR activation is modified differentially by protein kinase C-mediated effects. In particular, activation of protein kinase C in AC IV-transfected DDT1-MF2 cells eliminates the stimulatory input due to α2-AR activation. All of these observations indicate that the rise of intracellular Ca2+occurring at term in response to external stimuli (oxytocin, prostaglandin F2α, endothelins, acetylcholine through M3-muscarinic receptors, norepinephrine through α1-AR or α2B-AR) would reduce the synthesis of the smooth muscle relaxation mediator, i.e. cAMP, thereby allowing myometrial cells to contract.In conclusion, analysis of the functional properties of the AC population identified in the myometrium demonstrates for the first time that βγ complexes and Ca2+ are two main regulators of the AC/cAMP cascade during pregnancy in the rat. Because of similarities between human and rat myometrium with regard to AC types, as well as G proteins and membrane receptors, we postulate similar physiological regulations of the AC/cAMP system in human. Thus, cross-talks between various hormonal signals that are routed differentially through Gs, Gi, or Gq proteins according to the stage of pregnancy may dictate the final response of the AC/cAMP system and consequently the contractile state of the uterus. Data on hormonal regulation of myometrial contractility during the course of pregnancy implicate adenylyl cyclase (AC) 1The abbreviations used are: AC, adenylyl cyclases; AR, α2-adrenergic receptor; Gpp(NH)p, guanosine 5′-(β,γ-imido)triphosphate; kb, kilobases; GDPβS, guanyl-5′-yl thiophosphate. 1The abbreviations used are: AC, adenylyl cyclases; AR, α2-adrenergic receptor; Gpp(NH)p, guanosine 5′-(β,γ-imido)triphosphate; kb, kilobases; GDPβS, guanyl-5′-yl thiophosphate. stimulatory pathways as a key component that may affect the degree of intracellular cAMP generation and consequently the contractile state of the uterus. Because one of the major sites of control of the biochemical events leading to uterine relaxation during normal pregnancy lies at the AC/cAMP system, the identification of AC isoforms in the pregnant myometrium is essential in understanding the influence exerted by the regulatory external signals (neurotransmitters and hormones) acting via G protein-coupled receptors. Hormonal control of AC activity is brought about by receptor-catalyzed activation of heterotrimeric G proteins that in turn regulate the cyclases by the release of α or βγ subunits or kinase activation. Recent studies have revealed an unexpected diversity of G protein-regulated AC by identifying nine distinct AC cDNA from various mammalian tissues (1Krupinski J. Coussen F. Bakalyar H.A. Tang W.J. Feinstein P.G. Orth K. Slaughter C. Reed R.R. Gilman A.G. Science. 1989; 244: 1558-1564Crossref PubMed Scopus (505) Google Scholar, 2Yoshimura M. Cooper D.M.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 6716-6720Crossref PubMed Scopus (201) Google Scholar, 3Iyengar R. FASEB J. 1993; 7: 768-775Crossref PubMed Scopus (265) Google Scholar, 4Taussig R. Tang W.J. Hepler J.R. Gilman A.G. J. Biol. Chem. 1994; 269: 6093-6100Abstract Full Text PDF PubMed Google Scholar, 5Premont R.T. Matsuoka I. Mattei M.-G. Pouille Y. Defer N. Hanoune J. J. Biol. Chem. 1996; 271: 13900-13907Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). All of these isoforms of AC differ in their tissue distribution and their regulatory properties, providing a mode for different cells to respond diversely to similar external stimuli. Among all of the AC identified so far, the highly similar types II, IV, and VII form the largest known subfamily. Types II and IV share the property of being highly stimulated by βγ subunits of Gi/Goinhibitory proteins in the presence of activated Gsα (6Tang W.J. Gilman A.G. Science. 1991; 254: 1500-1503Crossref PubMed Scopus (741) Google Scholar,7Gao B. Gilman A.G. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 10178-10182Crossref PubMed Scopus (274) Google Scholar). These AC are also influenced by phosphorylation with protein kinase C (8Lustig K.D. Conklin B.R. Herzmark P. Taussig R. Bourne H.R. J. Biol. Chem. 1993; 268: 13900-13905Abstract Full Text PDF PubMed Google Scholar, 9Jacobowitz O. Chen J. Premont R.T. Iyengar R. J. Biol. Chem. 1993; 268: 3829-3832Abstract Full Text PDF PubMed Google Scholar, 10Zimmerman G. Taussig R. J. Biol. Chem. 1996; 271: 27161-27166Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 11Marjamaki A. Sato M. Bouet-Alard R. Yang Q. Limon-Boulez I. Legrand C. Lanier S.M. J. Biol. Chem. 1997; 272: 16466-16473Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). Types V and VI AC, a two-member subfamily, are inhibited directly by low levels of Ca2+ (2Yoshimura M. Cooper D.M.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 6716-6720Crossref PubMed Scopus (201) Google Scholar, 12Premont R.T. Chen J. Ma H.W. Ponnapali M. Iyengar R. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9809-9813Crossref PubMed Scopus (168) Google Scholar), whereas AC I and VIII are regulated positively by Ca2+-calmodulin (13Tang W.J. Krupinski J. Gilman A.G. J. Biol. Chem. 1991; 266: 8595-8603Abstract Full Text PDF PubMed Google Scholar, 14Cali J.J. Zwaagstra J.C. Mons N. Cooper D.M.F. Krupinski J. J. Biol. Chem. 1994; 269: 12190-12195Abstract Full Text PDF PubMed Google Scholar). On the other hand, AC III can be phosphorylated by a calmodulin-dependent protein kinase II in response to the elevation of intracellular Ca2+ which results, in vivo, in a 50% inhibition of hormone-stimulated enzyme (15Wei J. Wayman G. Storm D.R. J. Biol. Chem. 1996; 271: 24231-24235Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). The novel ninth AC is quite distinct from all of the other known AC subfamilies, and it is not affected by G βγ proteins or Ca2+ (5Premont R.T. Matsuoka I. Mattei M.-G. Pouille Y. Defer N. Hanoune J. J. Biol. Chem. 1996; 271: 13900-13907Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Thus, in vivo, when a cell type or tissue expresses various isoforms of AC one may expect that different physiological situations trigger different responses to the same external stimuli depending not only on the type of the receptor and G protein involved but also on the type of adenylyl cyclase to which they are coupled." @default.
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• W2068657810 title "Molecular Diversity of Adenylyl Cyclases in Human and Rat Myometrium" @default.
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