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A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior

ABSTRACT: A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior

PROVIDER: PRJNA886964 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21799058.fastq.gz	Fastqsanger.gz
	SRR21799059.fastq.gz	Fastqsanger.gz

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A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior

Project description:The single nucleotide polymorphism rs13166360, causing a substitution of valine 147 to leucine in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that this missense mutation diminishes ADCY2 activity by altering its subcellular localization. Mice homozygous for the leucine variant display signs of a mania-like state accompanied by cognitive impairments. Mutant mice are hypersensitive to amphetamine and mania-like behaviors are responsive to lithium treatment. Exposure to chronic social defeat stress switches homozygous leucine variant carriers from a mania- to a depressive-like state. Single-cell RNA-seq revealed widespread expression of ADCY2 in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as a BD risk gene providing insights into underlying disease mechanisms potentially opening novel avenues for therapeutic intervention strategies.

2024-12-26 | GSE214733 | GEO

Adenylyl cyclase 8, calmodulin - absolute quantification

Project description:The aim of this experiment was to absolutely quantify adenylyl cyclase 8 (AC8) and the co-purified interactor calmodulin (CaM) to assess their stoichiometry.

2024-02-14 | PXD044766 | Pride

Temporal and regional regulation of gene expression by calcium-stimulated adenylyl cyclase activity during fear memory

2010-10-19 | GSE23008 | GEO

A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior.

Project description:The single nucleotide polymorphism rs13166360, causing a substitution of valine (Val) 147 to leucine (Leu) in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3',5'-cylic adenosine monophosphate (cAMP) by altering its subcellular localization. We established mice specifically carrying the Val to Leu substitution using CRISPR/Cas9-based gene editing. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Mutant animals show additional characteristic signs of rodent mania models, i.e., they are hypersensitive to amphetamine, the observed mania-like behaviors are responsive to lithium treatment and the Val to Leu substitution results in a shifted excitatory/inhibitory synaptic balance towards more excitation. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which is reminiscent of the alternations characterizing the symptomatology in BD patients. Single-cell RNA-seq (scRNA-seq) revealed widespread Adcy2 mRNA expression in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as a BD risk gene, provide insights into underlying disease mechanisms, and potentially open novel avenues for therapeutic intervention strategies.

| S-EPMC11649569 | biostudies-literature

Transcriptional changes associated with chemical induction of adenylyl cyclase activity in Mtb

Project description:Transcriptional changes associated with chemical induction of adenylyl cyclase activity in Mtb

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Transcriptional profiling of monocytes of bipolar patients and controls

Project description:Bipolar disorder (BD) is a psychiatric disorder in which the core feature is pathological disturbance in mood ranging from extreme elation (mania) to severe depression. Study has shown an aberrant pro-inflammatory status of monocytes/macrophages in mood disorders. Therefore, this study aimed at studying the monocyte compartment in Bipolar Disorder, by transcription profiling of CD14+ monocytes in patients and controls.

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Adenylyl cyclase 3 deficiency results in the dysfunction of blood-testis barrier during mouse spermiogenesis

Project description:Human infertility has become a medical and social health problem globally. Mice deficient in type 3 adenylyl cyclase (AC3), a key enzyme that synthesizes cyclic adenosine monophosphate (cAMP), develop male infertility but its underlying molecular mechanisms are still unknown. Here, we performed label-free quantitative (LFQ) proteomics study to identify testicular differentially expressed proteins (DEPs) and their respective biological processes.

2021-07-19 | PXD027382 |

Temporal and regional regulation of gene expression by calcium-stimulated adenylyl cyclase activity during fear memory

Project description:Mice with the two calcium-stmulated adenylyl cyclase isoforms (AC1 and AC8; DKO mice) knocked-out show conditioned fear memory deficits. We assessed gene expression changes at baseline and several time points after conditioned fear learning to assess transcriptional changes at different stages of learning. Transcriptional changes were assessed in the amydgdala and hippocampus of DKO and wild-type mice. Mice either received no treatment (baseline) or were subjected to conditioned fear training (one 0.7mA x 2 sec shock). Amygdala and hippocampal tissue from wild-type and DKO (AC1 and AC8 KO) mice was used. Samples were extracted at baseline (-5 min before conditioned fear training), 0 hr, 1 hr, or 48 hr after a 5 min conditioned fear training trial, or at 1 wk after a 5 min conditioned fear testing trial. RNA samples from 5-10 mice were pooled per array with one array per genotype/brain region/time point for a total of 20 arrays. mRNA was reverese transcribed, labeled and hybridized to Affymetric Mouse Gene ST 1.0 Arrays.

2010-10-19 | E-GEOD-23008 | biostudies-arrayexpress

The protein phosphatase 2C domain contributes to the pathobiological function of adenylyl cyclase in Cryptococcus neoformans

Project description:Adenylyl cyclase (AC) is the central regulator of cAMP signalling in fungal pathogens, yet fungal ACs uniquely contain a protein phosphatase 2C (PP2C) domain whose function remains unclear. Here, we characterise the PP2C domain of the AC Cac1 in the human pathogen Cryptococcus neoformans. Structural and biochemical analyses show that Cac1-PP2C adopts a non-canonical scaffold but functions as a Ser/Thr-specific metalloenzyme. Deletion of the PP2C or AC catalytic (ACC) domain demonstrated that PP2C is required for full Cac1 activity, influencing melanin and capsule synthesis, sexual differentiation, titan cell formation, and cell wall integrity. Notably, the PP2C-null mutant induced Th2-biased immunity and extensive pulmonary damage yet failed to cause mortality in mice. Integrated transcriptomic and phosphoproteomic analyses further revealed shared and domain-specific signalling outputs mediated by PP2C and ACC. This study provides the first comprehensive characterisation of a fungal AC-linked PP2C domain and defines its pivotal role in C. neoformans pathobiology

2025-12-09 | GSE312692 | GEO

Interactome analysis of Adenylyl cyclase-associated protein 1

Project description:The direct inflammatory action of proprotein convertase subtilisin/kexin type 9 (PCSK9) is examined in vitro in monocytes and endothelial cells, as well as via an in vivo atherosclerosis animal model. PCSK9 exacerbates atherosclerosis in low-density lipoprotein receptor (LDLR)-/- mice, indicating an inflammatory effect mediated independently of the LDLR pathway. Here we show that Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9, serving a crucial role in the pro-inflammatory cascade of PCSK9 by enabling the induction of cytokines, the activation of Toll-like receptor 4 (TLR4), and the upregulation of scavenger receptors. We also present spleen tyrosine kinase (Syk) and protein kinase C delta (PKCδ) as pivotal mediators in the inflammatory cascade subsequent to PCSK9-CAP1 binding. In human peripheral blood mononuclear cells (PBMCs), serum PCSK9 levels are positively correlated with Syk, PKCδ, and p65 phosphorylation. Notably, the CAP1-fragment crystallizable region (CAP1-Fc) shows superior efficacy in mitigating PCSK9-mediated inflammatory signal transduction when compared with the PCSK9 inhibitor, evolocumab.

2024-06-16 | PXD047058 | Pride

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