Adenylyl cyclase type-VIII activity is regulated by Gβγ subunits

Steiner, Debora; Saya, Daniella; Schallmach, Ester; Simonds, William F.; Vogel, Zvi

doi:10.1016/j.cellsig.2005.03.014

Cited by 42 publications

(20 citation statements)

References 49 publications

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“…In these experiments, the C terminus of G protein-coupled receptor kinase 2 (GRK2-CT) that contains the G␤␥ binding domain was overexpressed in COS-7 cells to sequester the G␤␥ subunits that are released upon activation of ␤-adrenergic receptors by isoproterenol. This approach has previously been used to examine the role of G␤␥ subunits in regulation of effectors such as phospholipase C-␤, ACII, ACVIII, and activation of the mitogen-activated protein kinase cascade (32,43,44). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Upon receptor-mediated activation and dissociation of heterotrimeric G protein components, the G␤␥ subunits have been shown to modulate the activities of several effectors including phospholipase C-␤, GRK2, and certain isoforms of adenylyl cyclases such as ACI, ACII, ACIII, ACIV, ACVII, and ACVIII (13,32). Among the AC isoforms, G␤␥ stimulates the activity of ACII, ACIV, and ACVII, provided some active G␣ s is present (13).…”

Section: Discussionmentioning

confidence: 99%

“…The known G␤␥ effectors include phospholipases (28), ion channels (29), G protein-coupled receptor kinases (30), phosphoinositide 3-kinases (31), and some isoforms of AC. Among the AC isoforms, ACII, ACIV, and ACVII are stimulated by G␤␥ subunits provided that some G␣ s is present (13), whereas ACI and ACVIII are inhibited by G␤␥ (13,32).…”

mentioning

confidence: 99%

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Conditional Stimulation of Type V and VI Adenylyl Cyclases by G Protein βγ Subunits

Gao

Sadana

Dessauer

et al. 2007

Journal of Biological Chemistry

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In a yeast two-hybrid screen of mouse brain cDNA library, using the N-terminal region of human type V adenylyl cyclase (hACV) as bait, we identified G protein ␤2 subunit as an interacting partner. Additional yeast two-hybrid assays showed that the G␤ 1 subunit also interacts with the N-terminal segments of hACV and human type VI adenylyl cyclase (hACVI). In vitro adenylyl cyclase (AC) activity assays using membranes of Sf9 cells expressing hACV or hACVI showed that G␤␥ subunits enhance the activity of these enzymes provided either G␣ s or forskolin is present. Deletion of residues 77-151, but not 1-76, in the N-terminal region of hACVI obliterated the ability of G␤␥ subunits to conditionally stimulate the enzyme. Likewise, activities of the recombinant, engineered, soluble forms of ACV and ACVI, which lack the N termini, were not enhanced by G␤␥ subunits. Transfection of the C terminus of G protein receptor kinase 2 to sequester endogenous G␤␥ subunits attenuated the ability of isoproterenol to increase cAMP accumulation in COS-7 cells overexpressing hACVI even when G i was inactivated by pertussis toxin. Therefore, we conclude that the N termini of human hACV and hACVI are necessary for interactions with, and regulation by, G␤␥ subunits both in vitro and in intact cells. Moreover, G␤␥ subunits derived from a source(s) other than G i are necessary for the full activation of hACVI by isoproterenol in intact cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Conditional Stimulation of Type V and VI Adenylyl Cyclases by G Protein βγ Subunits

Gao

Sadana

Dessauer

et al. 2007

Journal of Biological Chemistry

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“…The ␤ARK-ct construct only effectively increased the cAMP response at 30 min, perhaps indicative of the time required for G-␤␥ subunits to effectively inhibit cAMP production. There is evidence for G-␤␥ inhibition of adenylate cyclase, specifically types I (Tang and Gilman, 1991), V and VI (Bayewitch et al, 1998b), and VIII (Steiner et al, 2006). Thus, this is likely the mechanism responsible for the observed cAMP inhibition by G-␤␥ subunits.…”

mentioning

confidence: 95%

Relaxin Family Peptide Receptors RXFP1 and RXFP2 Modulate cAMP Signaling by Distinct Mechanisms

Halls¹,

Bathgate²,

Summers³

2006

Mol Pharmacol

121

176

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Two orphan leucine-rich repeat-containing G protein-coupled receptors were recently identified as targets for the relaxin family peptides relaxin and insulin-like peptide (INSL) 3. Human gene 2 relaxin is the cognate ligand for relaxin family peptide receptor (RXFP) 1, whereas INSL3 is the ligand for RXFP2. Constitutively active mutants of both receptors when expressed in human embryonic kidney (HEK) 293T cells signal through G␣ s to increase cAMP. However, recent studies using cells that endogenously express the receptors revealed greater complexity: cAMP accumulation after activation of RXFP1 involves a time-dependent biphasic pathway with a delayed phase involving phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC) , whereas the RXFP2 response involves inhibition of adenylate cyclase via pertussis toxin-sensitive G proteins. The aim of this study was to compare and contrast the cAMP signaling pathways used by these two related receptors. In HEK293T cells stably transfected with RXFP1, preliminary studies confirmed the biphasic cAMP response, with an initial G␣ s component and a delayed response involving PI3K and PKC. This delayed pathway was dependent upon G-␤␥ subunits derived from G␣ i3 . An additional inhibitory pathway involving G␣ oB affecting cAMP accumulation was also identified. In HEK293T cells stably transfected with RXFP2, the cAMP response involved G␣ s and was modulated by inhibition mediated by G␣ oB and release of inhibitory G-␤␥ subunits. Thus, initially both RXFP1 and RXFP2 couple to G␣ s and an inhibitory G␣ oB pathway. Differences in cAMP accumulation stem from the ability of RXFP1 to recruit coupling to G␣ i3 , release G-␤␥ subunits and thus activate a delayed PI3K-PKC pathway to further increase cAMP accumulation.Relaxin is a two-chain peptide hormone that is structurally closely related to insulin. It belongs to the insulin-relaxin peptide family that includes the relaxins: human gene (H)1 (product of a gene duplication event in higher primates), H2 (major circulating form), and H3 (principally a neuropeptide); insulin; insulin-like growth factors I and II; and the relaxin/insulin-like factors INSL3, INSL4, INSL5, and INSL6. Although relaxin was first identified for its role in parturition in guinea pigs (Hisaw, 1926), it is now recognized as a hormone with pleiotropic effects. Relaxin has important functions in the heart, kidney, and brain in addition to roles in the regulation of nitric oxide production and neoangiogenesis (for review, see Bathgate et al., 2006). It is noteworthy that relaxin can also prevent the tissue remodeling observed in fibrosis with a conservation of endogenous tissue structure , and herein lies its potential as a therapeutic.Despite the length of time since the discovery of relaxin, its receptor remained elusive until the recent pairing of relaxin family peptides with two highly similar leucine-rich repeatcontaining GPCRs: LGR7 and LGR8 . LGR7 was subsequently identified as the relaxin receptor and LGR8 as the receptor for the related peptide ...

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“…Furthermore there is a highly cited paper that shows inhibition of ACs by Gbg in membranes from brain (Chen et al 1995), although this does not distinguish between AC1 and AC8. Apart from this study, only one other documents AC8 inhibition by Gbg subunits, which was conducted in whole cells overexpressing the enzyme (Steiner et al 2006). The evidence for AC3 regulation by Gbg is conflicting and sparse; two studies in overexpression systems have reported no effect Marjamaki et al 1997), whereas another reports inhibition (Diel et al 2006).…”

Section: Inhibition Of Ac1 Ac3 and Ac8 By Gbgmentioning

confidence: 99%