Adenylyl cyclases: structure, regulation and function in an enzyme superfamily

Hanoune, Jacques; Pouille, Yves; Tzavara, Eleni T.; Shen, Tiansheng; Lipskaya, Larissa; Miyamoto, Noboru; Suzuki, Yosuke; Defer, Nicole

doi:10.1016/s0303-7207(97)04013-6

Cited by 147 publications

(98 citation statements)

References 97 publications

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“…This additional mechanism of action of G proteins seems to occur with high selectivity. For instance, whereas bg inhibits type I adenylyl cyclase activity, this complex greatly potentiates the stimulatory effect of Gs on both type II and IV adenylyl cyclase and is ineffective on the other isozymes (17,18). Moreover, among the different b and g subunits so far cloned, the bg of the Gi family seems to be frequently involved in the modulation of intracellular effectors involved in cell proliferation (19±21).…”

Section: G Protein Structure and Functionmentioning

confidence: 99%

G protein mutations in endocrine diseases

Lania

Mantovani

Spada

2001

European Journal of Endocrinology

100

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This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in endocrine diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identi®ed which harbor naturally occurring mutations, Gsa, the activator of adenylyl cyclase and Gi2a, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gsa (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-speci®c hormone resistance observed in PHP Ia may result from tissuespeci®c imprinting of the GNAS1 gene, although the Gsa knockout model only in part reproduces the human AHO phenotype. Activating somatic Gsa mutations leading to cell proliferation have been identi®ed in endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e. GH-secreting pituitary adenomas, hyperfunctioning thyroid adenomas and Leydig cell tumors. When the same mutations occur very early in embryogenesis they cause McCune±Albright syndrome. Although these mutations would in principle confer growth advantage, studies failed to detect differences in the clinical and hormonal phenotypes, suggesting the existence of mechanisms able to counteract the activation of the cAMP pathway. Activating mutations of Gi2a have been identi®ed in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and signi®cance are still controversial. Finally, although Ga subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, b/g subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of b3 subunit variants in patients with essential hypertension.

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Section: G Protein Structure and Functionmentioning

confidence: 99%

G protein mutations in endocrine diseases

Lania

Mantovani

Spada

2001

European Journal of Endocrinology

100

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“…Such differential expression imply that the same stimuli, the forskolin treatment, resulted in different effects on the expression of each AC isoform, reflecting the fact that mammalian AC's are encoded by at least 9 separate genes which are not clustered, and localized on different chromosomes in the human genomes (Hanoune et al, 1997). The promoter regions of all the AC genes are not known, but the expression of individual AC isoform, based our results, would likely be regulated by different mechanisms.…”

Section: Discussionmentioning

confidence: 77%

“…AC isoforms have different kinetic and regulatory properties, such as regulation by inhibitory G proteins, betagamma subunits of G proteins, calcium, calmodulin, and protein kinases (Hanoune et al, 1997). Thus the observed differential increase in the expression of AC isoforms may result in both the increase of the enzyme activity and the changes in the regulatory properties in the melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Multi-facet expressions of adenylate cyclase isoforms in B16-F10 melanoma cells differentiated by forskolin treatment

Cho

Bae²,

Juhnn³

2000

Exp Mol Med

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The terminal differentiation of malignant melanoma cells is known to be induced by activating cAMP signaling pathway with α-MSH or cAMP analogues. However, sustained activation of cAMP signaling system that induces the differentiation of melanoma cells, also induces the desensitization of the pathway at the receptor level. Nevertheless, the adaptation of adenylate cyclase (AC) expression by sustained activation of cAMP signaling system has not been clearly understood. This study was performed to examine whether the sustained activation of cAMP system induce changes in the expression AC isoforms as an adaptation mechanism. Treatment of B16/F10 murine melanoma cells with 100 mM forskolin for 6 days resulted in differentiation, melanin accumulation and increased expression of tyrosine hydroxylase mRNA. In the forskolin-treated melanoma cells, change in expression of various AC isoform at the transcription level was detected by reverse-transcription polymerase chain reaction (RT-PCR). Expression of AC isoform mRNA: ACI, III, VI, VII, and IX increased to the level of 196-392% of the control whereas the level of ACII was decreased by 30%. The cAMP concentration was increased both in basal and α-MSH stimulated cells, but the AC activity was decreased in the forskolin treated cells. Thus, these results suggest that sustained activation of cAMP system induces differential expression of AC isoforms, which results in increase of cAMP accumulation.

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“…Why was β 1 -ARmediated cAMP production enhanced by MβCD treatment? Neonatal cardiomyocytes express two types of adenylyl cyclase: adenylyl cyclase type 5 (AC-V) and type 6 (AC-VI) (23). These subtypes of AC distribute over the caveolae and other cell fractions.…”

Section: Discussionmentioning

confidence: 99%

Caveolae-Independent Activation of Protein Kinase A in Rat Neonatal Myocytes

et al. 2005

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Abstract. Cardiomyocytes express both β 1 -and β 2 -adrenergic receptors, and these receptors play a differential role in chronotropic and inotropic effects of the heart. Caveolae are known as an important regulator of G-protein-coupled receptor signaling. In the present report, we examined whether caveolae have a role in β-adrenergic receptor-stimulated cAMP production and protein kinase A activation in neonatal myocytes. Isoproterenol-stimulated cAMP production was mediated by β 1 -and β 2 -subtypes, which depends on the receptor number of each subtype. However, protein kinase A activation was exclusively mediated by the β 1 -subtype. Disruption of caveolae by methyl-β-cyclodextrin treatment did not affect the relative contribution of subtypes to isoproterenol-stimulated cAMP production. β 1 -Subtype-mediated protein kinase A activation was also not affected by the disruption of caveolae. These results suggest that β 1 -adrenergic receptor-mediated protein kinase A activation is compartmentalized and independent of caveolae.

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Adenylyl cyclases: structure, regulation and function in an enzyme superfamily

Cited by 147 publications

References 97 publications

G protein mutations in endocrine diseases

G protein mutations in endocrine diseases

Multi-facet expressions of adenylate cyclase isoforms in B16-F10 melanoma cells differentiated by forskolin treatment

Caveolae-Independent Activation of Protein Kinase A in Rat Neonatal Myocytes

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