Type 7 Adenylyl Cyclase-Mediated Hypothalamic-Pituitary-Adrenal Axis Responsiveness: Influence of Ethanol and Sex

Pronko, Sergey P.; Saba, Laura; Hoffman, Paula L.; Tabakoff, Boris

doi:10.1124/jpet.110.166793

Cited by 20 publications

(20 citation statements)

References 35 publications

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“…Recent data suggest that CRF1 activation increases the enzymatic activity of AC7 (Antoni et al, 2003; Pronko et al, 2010). Therefore, we explored the possible role of AC7 in CRF-dependent stimulation of GABA release in the CeA.…”

Section: Resultsmentioning

confidence: 99%

Type 7 Adenylyl Cyclase is Involved in the Ethanol and CRF Sensitivity of GABAergic Synapses in Mouse Central Amygdala

Cruz¹,

Bajo²,

Maragnoli³

et al. 2011

Front. Neurosci.

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The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and in the anxiogenic response to ethanol withdrawal. Previously, we found that both ethanol and corticotropin releasing factor (CRF) increase GABAergic transmission in mouse and rat CeA neurons, in part by enhancing the release of GABA via activation of presynaptic CRF1 receptors. CRF1 receptors are coupled to the enzyme adenylyl cyclase (AC), which produces the second messenger cyclic AMP. There are nine isoforms of AC, but we recently found that CRF1 receptors in the pituitary were coupled to the Type 7 AC (AC7). Therefore, using an in vitro electrophysiological approach in brain slices, here we have investigated a possible role of the AC7 signaling pathway in ethanol and CRF effects on CeA GABAergic synapses of genetically modified mice with diminished brain Adcy7 activity (HET) compared to their littermate male wild-type (WT) mice. We found no significant differences in basal membrane properties, mean baseline amplitude of evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs), or paired-pulse facilitation (PPF) of GABAA-IPSPs between HET and WT mice. In CeA neurons of WT mice, ethanol superfusion significantly augmented (by 39%) GABAA-IPSPs and decreased PPF (by 25%), suggesting increased presynaptic GABA release. However, these effects were absent in HET mice. CRF superfusion also significantly augmented IPSPs (by 38%) and decreased PPF (by 23%) in WT CeA neurons, and still elicited a significant but smaller (by 13%) increase of IPSP amplitude, but no effect on PPF, in HET mice. These electrophysiological data suggest that AC7 plays an important role in ethanol and CRF modulation of presynaptic GABA release in CeA and thus may underlie ethanol-related behaviors such as anxiety and dependence.

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Section: Resultsmentioning

confidence: 99%

Type 7 Adenylyl Cyclase is Involved in the Ethanol and CRF Sensitivity of GABAergic Synapses in Mouse Central Amygdala

Cruz¹,

Bajo²,

Maragnoli³

et al. 2011

Front. Neurosci.

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“…AIP protein was also found to interact with two specific Ga 13 and Ga q . Although these two proteins were initially thought to have no effect on cAMP signalling, one study reported that Ga 13 activates an isoform of adenylate cyclase, type VII (AC7), which is partially responsible for cAMP production in a number of cells, including the pituitary (Jiang et al 2007, Pronko et al 2010. Given the lack of data with regard to interaction of the AIP protein with these four proteins, the effect of overexpression or knock down of AIP on cAMP signalling is a matter of speculation.…”

Section: Discussionmentioning

confidence: 99%

Aip regulates cAMP signalling and GH secretion in GH3 cells

Formosa¹,

Xuereb-Anastasi²,

Vassallo³

2013

Endocrine-Related Cancer

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Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been linked to predisposition to pituitary adenomas. However, the mechanism by which this occurs remains unknown. AIP interacts with a number of interesting proteins, including members of the cAMP signalling pathway that has been shown to be consistently altered in pituitary tumours. The functional role of Aip was investigated using both over-expression and knock down of Aip in GH3 cells. cAMP signalling and its downstream effectors, including GH secretion, were then investigated. cAMP signalling was analysed using cAMP assays, cAMP-response element-promoter luciferase reporter assays, real-time PCR and finally secreted GH quantification. Over-expression of wild-type (WT)-Aip reduced forskolin-induced cAMP signalling at the total cAMP level, luciferase reporter activity and target gene expression, when compared with empty vector and the non-functional R304X mutant. Additionally, GH secretion was reduced in WT-Aip over-expressing GH3 cells treated with forskolin. Knock down of endogenous Aip resulted in increased cAMP signalling but a decrease in GH secretion was also noted. Inhibition of phosphodiesterase activity using general and selective inhibitors did not completely ablate the effect of Aip on forskolin-augmented cAMP signalling. A mechanism by which Aip acts as a tumour suppressor, by maintaining a low cAMP signalling and concentration, is suggested. Mutations of Aip render the protein incapable of such activity. This effect appears not to be mediated by the AIP-PDE interaction, suggesting the involvement of other interacting partners in mediating this outcome.

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“…cAMP is produced from ATP by adenylyl cyclase, a large family of proteins including ten isoforms encoded by ten different genes and classified in five families (reviewed by Sunahara & Taussig (2002)). Mouse pituitaries express mRNA for adenylyl cyclase isoforms II, III, VI, and VII (Pronko et al 2010), depending on the cell type. In particular, GHproducing cells (GH1 2 C 1 cells) mainly contain adenylyl cyclase types I, III (calcium-calmoduline sensitive), and VI, whereas cells predominantly secreting PRL express adenylyl cyclase types II, IV, and VI (GH3 and GH4C1 cells) and type VIII (GH3B6 cells) (Paulssen et al 1994, Wachten et al 2010.…”

Section: Introductionmentioning

confidence: 99%

cAMP in the pituitary: an old messenger for multiple signals

Peverelli¹,

Mantovani²,

Lania³

et al. 2013

Journal of Molecular Endocrinology

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The cyclic nucleotide cAMP is a universal regulator of a variety of cell functions in response to activated G-protein coupled receptors. In particular, cAMP exerts positive or negative effects on cell proliferation in different cell types. As demonstrated by several in vitro studies, in somatotrophs and in other endocrine cells, cAMP is a mitogenic factor. In agreement with this notion, it has been found that the mutations of genes coding for proteins that contribute to increases in the cAMP signaling cascade may cause endocrine tumor development. This review will discuss the central role of cAMP signaling in the pituitary, focusing on the cAMP pathway alterations involved in pituitary tumorigenesis, as well as on poorly investigated the aspects of cAMP cascade, such as crosstalk with the ERK signaling pathway and new cAMP effectors.

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Type 7 Adenylyl Cyclase-Mediated Hypothalamic-Pituitary-Adrenal Axis Responsiveness: Influence of Ethanol and Sex

Cited by 20 publications

References 35 publications

Type 7 Adenylyl Cyclase is Involved in the Ethanol and CRF Sensitivity of GABAergic Synapses in Mouse Central Amygdala

Type 7 Adenylyl Cyclase is Involved in the Ethanol and CRF Sensitivity of GABAergic Synapses in Mouse Central Amygdala

Aip regulates cAMP signalling and GH secretion in GH3 cells

cAMP in the pituitary: an old messenger for multiple signals

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