Cloning, Chromosomal Mapping, and Regulatory Properties of the Human Type 9 Adenylyl Cyclase (ADCY9)

Hacker, Beth M.; Tomlinson, James; Wayman, Gary A.; Sultana, Razia; Chan, Guy C.‐K.; Villacres, Enrique C.; Distèche, Christine M.; Storm, Daniel R.

doi:10.1006/geno.1998.5293

Cited by 98 publications

(103 citation statements)

References 27 publications

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“…However, because ACIX is the only AC known to exhibit this particular behavior in response to G␣ s /forskolin costimulation when expressed in HEK293 cells, this explanation is unlikely. As previously proposed by Hacker et al (1998), we favor a mechanism in which the binding of forskolin to ACIX renders the enzyme resistant to G␣ s stimulation (Hacker et al, 1998). Because we also found that fMLP stimulation of AC is not altered by forskolin, we propose that signals downstream of chemotactic and ␤-adrenergic receptors act on distinct sites of ACIX.…”

supporting

confidence: 78%

“…ACIX is the most divergent isoform of ACs and constitutes a separate subfamily of ACs (Tang and Hurley, 1998;Sunahara and Taussig, 2002). Like all transmembrane ACs, ACIX is stimulated by G␣ s , but unlike ACI-ACVIII, ACIX is insensitive to forskolin stimulation, a diterpene from the plant Coleus forskohlii (Premont et al, 1996;Hacker et al, 1998). In mammalian cells, the canonical pathway leading to AC activation involves the activation of the heterotrimeric G proteins G␣ s ␤␥.…”

Section: Introductionmentioning

confidence: 99%

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A Chemoattractant-mediated G_i-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

Mahadeo

Janka-Junttila

Smoot

et al. 2007

MBoC

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Neutrophils and Dictyostelium use conserved signal transduction pathways to decipher chemoattractant gradients and migrate directionally. In both cell types, addition of chemoattractants stimulates the production of cAMP, which has been suggested to regulate chemotaxis. We set out to define the mechanism by which chemoattractants increase cAMP levels in human neutrophils. We show that chemoattractants elicit a rapid and transient activation of adenylyl cyclase (AC). This activation is sensitive to pertussis toxin treatment but independent of phosphoinositide-3 kinase activity and an intact cytoskeleton. Remarkably, and in sharp contrast to G␣ s -mediated activation, chemoattractant-induced AC activation is lost in cell lysates. Of the nine, differentially regulated transmembrane AC isoforms in the human genome, we find that isoforms III, IV, VII, and IX are expressed in human neutrophils. We conclude that the signal transduction cascade used by chemoattractants to activate AC is conserved in Dictyostelium and human neutrophils and is markedly different from the canonical G␣ s -meditated pathway. INTRODUCTIONMany types of cells have the ability to migrate directionally when exposed to gradients of chemoattractants. This chemotactic response is essential for a variety of physiological processes and is initiated when chemoattractants bind surface receptors and activate a wide range of signal transduction cascades, which ultimately lead to cellular polarization and migration (Parent, 2004). The acquisition of polarity is accompanied by a dramatic redistribution of cytoskeletal components, where F-actin and numerous actin-binding proteins are enriched at the front or leading edge and myosin II is assembled on the sides and at the back or trailing edge (Van Haastert and Devreotes, 2004;Bagorda et al., 2006).A striking chemotactic behavior is exhibited by neutrophils as they move across vascular barriers and navigate to sites of inflammation (Niggli, 2003b;Parent, 2004). The agents that induce directed migration of neutrophils include a large and diverse group of chemoattractants originating from different sources (Uhing and Snyderman, 1999). These agents include formylated peptides secreted by bacteria (such as N-formylmethionyl-leucyl-phenylalanine [fMLP]), products of the complement cascade (such as complement factor 5a [C5a]), and phospholipid metabolites (such as leukotriene B4 [LTB 4 ]) as well as a large family of chemokines that are derived from endothelial, epithelial, and stromal cells (Baggiolini, 1998). Remarkably, neutrophils can also relay the signal to surrounding cells by stimulating the production and release of more attractants, such as LTB 4 and interleukin (IL)-8, which act in a paracrine manner to spread the chemotactic response to surrounding cells (Bazzoni et al., 1991;Baggiolini et al., 1994;Kannan, 2002). Chemoattractants bind to serpentine transmembrane receptors that couple to heterotrimeric G proteins (Murphy, 1996). Receptor activation leads to the dissociation of the G protein into ␣-and...

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supporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

A Chemoattractant-mediated G_i-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

Mahadeo

Janka-Junttila

Smoot

et al. 2007

MBoC

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“…Oligonucleotide primers specifically designed to be complementary to the cDNA sequence of human ACs, rather than rat, murine or bovine sequences, have been employed to demonstrate the presence of mRNA encoding for a variety of AC isoforms. At present, human sequence data exist for only five AC isoforms, namely AC I (Villacres et al 1993), AC II (Stengel et al 1992), AC III (Yang et al 1999), AC VIII (Defer et al 1994) and AC IX (Hacker et al 1998). By utilising primers based on these published human sequences we have demonstrated the presence of mRNA encoding for Groups 1 (types I, III and VIII), 2 (AC II) and 4 (AC IX) in both pregnant and non-pregnant human myometrium.…”

Section: Discussionmentioning

confidence: 85%

“…In addition, the Group 4 isoform AC IX has been found to be insensitive to forskolin stimulation (Hacker et al 1998, Yan et al 1998 suggesting that forskolin binding studies alone are not sufficient to monitor alterations in AC expression. Using immunoblotting techniques we have now demonstrated that whilst there are no topographical differences in uterine AC isoform expression, there are changes during pregnancy in the relative expression of the various isoforms of AC as membrane-associated protein.…”

Section: Figurementioning

confidence: 99%

Adenylyl cyclase isoforms in pregnant and non-pregnant human myometrium

Price

Pochun²,

Phaneuf³

et al. 2000

Journal of Endocrinology

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The precise factors involved in the transition of the relaxed pregnant uterus to the contractile state at the onset of parturition remain unclear, but it is accepted that cAMPgenerating pathways contribute to uterine relaxation. We have previously reported an increased expression of the adenylyl cyclase (AC)-stimulating protein G s in human myometrium during gestation, with a corresponding increase in GTP-stimulated AC activity. However, little is known about the predominating AC isoforms expressed during pregnancy. This information is important, because although all AC isoforms are stimulated by G s, their regulation by other signalling molecules is very different. In the present study we have identified the isoforms of AC expressed in both pregnant and non-pregnant myometrium by mRNA analysis and immunoblotting. mRNA encoding for AC I, II, III, VIII and IX was present in non-pregnant and pregnant myometrium, and in cultured myometrial cells. Differing levels of AC protein could be detected in myometrial plasma membranes, with decreased levels of Group 1 (isoforms I, III and VIII) and Group 4 (IX) ACs allied with increased levels of Group 2 (II, IV and VII) and 3 (V and VI) ACs during pregnancy. These findings imply a role for Group 2-activating pathways, e.g. G-protein -subunits and protein kinase C, in the maintenance of uterine quiescence, whilst suggesting a lesser involvement of calcium-calmodulin complex, an activator of Group 1 AC isoforms, in uterine relaxation during gestation. These data may provide an alternative pharmacological approach for the attenuation of preterm labour.

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“…110,111 It occupies part of the second, degenerated "active site" in tmACs (Figure 4(a)), 40 and it has been speculated to exploit the binding site of an as yet unidentified endogenous regulatory ligand. Forskolin has been suggested to activate tmACs by inducing dimerization and/or active site rearrangements, 40 but this idea remains speculative because the structure of a tmAC in the absence of forskolin is not yet known.…”

Section: Regulation By Small Molecules Forskolinmentioning

confidence: 99%

Molecular Details of cAMP Generation in Mammalian Cells: A Tale of Two Systems

Kamenetsky

Middelhaufe

Bank

et al. 2006

Journal of Molecular Biology

293

340

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The second messenger cAMP has been extensively studied for half a century, but the plethora of regulatory mechanisms controlling cAMP synthesis in mammalian cells is just beginning to be revealed. In mammalian cells, cAMP is produced by two evolutionary related families of adenylyl cyclases, soluble adenylyl cyclases (sAC) and transmembrane adenylyl cyclases (tmAC). These two enzyme families serve distinct physiological functions. They share a conserved overall architecture in their catalytic domains and a common catalytic mechanism, but they differ in their sub-cellular localizations and responses to various regulators. The major regulators of tmACs are heterotrimeric G proteins, which transduce extracellular signals via G protein-coupled receptors. sAC enzymes, in contrast, are regulated by the intracellular signaling molecules bicarbonate and calcium. Here, we discuss and compare the biochemical, structural and regulatory characteristics of the two mammalian AC families. This comparison reveals the mechanisms underlying their different properties but also illustrates many unifying themes for these evolutionary related signaling enzymes.

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Cloning, Chromosomal Mapping, and Regulatory Properties of the Human Type 9 Adenylyl Cyclase (ADCY9)

Cited by 98 publications

References 27 publications

A Chemoattractant-mediated G_i-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

A Chemoattractant-mediated G_i-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

Adenylyl cyclase isoforms in pregnant and non-pregnant human myometrium

Molecular Details of cAMP Generation in Mammalian Cells: A Tale of Two Systems

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Cloning, Chromosomal Mapping, and Regulatory Properties of the Human Type 9 Adenylyl Cyclase (ADCY9)

Cited by 98 publications

References 27 publications

A Chemoattractant-mediated Gi-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

A Chemoattractant-mediated Gi-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

Adenylyl cyclase isoforms in pregnant and non-pregnant human myometrium

Molecular Details of cAMP Generation in Mammalian Cells: A Tale of Two Systems

Contact Info

Product

Resources

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A Chemoattractant-mediated G_i-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

A Chemoattractant-mediated G_i-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils