Dataset Information

A cAMP signaling model explains the benefit of maintaining two forms of phosphodiesterase in Dictyostelium.

ABSTRACT: Starving Dictyostelium cells respond chemotactically to cell-generated waves of cyclic adenosine -3',5'- monophosphate (cAMP) that guide cell aggregation toward a signaling center. In this process, a large number of cells are recruited, resulting in the formation of aggregation territories that are essential for fruiting body formation. The enzyme PdsA phosphodiesterase (PDE), a crucial component of the signaling system, breaks down the external cAMP and can be either membrane-bound or secreted. The existence of two such forms is unusual in cell biology, and it remains to be determined why they have both been maintained through evolution. Here, using a model of the cAMP signaling system, I show that colonies can successfully organize into aggregates over a wider range of initial cell densities when both forms of PDE are present in an appropriately tuned ratio than when only a single form is present. The model indicates that membrane-bound PDE maintains aggregation-territory integrity in colonies with high initial cell density, whereas the secreted form is important for wave propagation at low cell densities. Thus, the ultimate retention of both forms can increase territory size. These findings have implications for other excitable media, including Ca(2+) propagation in cardiac cells and propagation of electrical excitation in nerve axons, since these systems have similar features of spatial nonuniform "release" and "degradation" of the relevant signals.

SUBMITTER: Palsson E

PROVIDER: S-EPMC2771350 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A cAMP signaling model explains the benefit of maintaining two forms of phosphodiesterase in Dictyostelium.

Pálsson Eiríkur E

Biophysical journal 20091101 9

Starving Dictyostelium cells respond chemotactically to cell-generated waves of cyclic adenosine -3',5'- monophosphate (cAMP) that guide cell aggregation toward a signaling center. In this process, a large number of cells are recruited, resulting in the formation of aggregation territories that are essential for fruiting body formation. The enzyme PdsA phosphodiesterase (PDE), a crucial component of the signaling system, breaks down the external cAMP and can be either membrane-bound or secreted. ...[more]

PMID: 19883581

Similar Datasets

Project description:Cyclic AMP (cAMP) is an important intracellular signaling molecule for many G protein-mediated signaling pathways but the specificity of cAMP signaling in cells with multiple signaling pathways is not well-understood. In Dictyostelium, at least two different G protein signaling pathways, mediated by the G?2 and G?4 subunits, are involved with cAMP accumulation, spore production, and chemotaxis and the stimulation of these pathways results in the activation of ERK2, a mitogen-activated protein kinase that can down regulate the cAMP-specific phosphodiesterase RegA. The regA gene was disrupted in g?2(?) and g?4(?) cells to determine if the absence of this phosphodiesterase rescues the development of these G protein mutants as it does for erk2(?) mutants. There gA(?) mutation had no major effects on developmental morphology but enriched the distribution of the G? mutant cells to the prespore/prestalk border in chimeric aggregates. The loss of RegA function had no effect on G?4- mediated folate chemotaxis. However, the regA gene disruption in g?4(?) cells, but not in g?2(?) cells, resulted in a substantial rescue and acceleration of spore production. This rescue in sporulation required cell autonomous signaling because the precocious sporulation could not be induced through intercellular signaling in chimeric aggregates. However, intercellular signals from regA(?) strains increased the expression of the prestalk gene ecmB and accelerated the vacuolization of stalk cells. Intercellular signaling from the g?4(?)regA(?) strain did not induce ecmA gene expression indicating cell-type specificity in the promotion of prestalk cell development. regA gene disruption in a G?4(HC) (G?4 overexpression) strain did not result in precocious sporulation or stalk cell development indicating that elevated G?4 subunit expression can mask regA(?) associated phenotypes even when provided with wild-type intercellular signaling. These findings indicate that the G?2 and G?4-mediated pathways provide different contributions to the development of spores and stalk cells and that the absence of RegA function can bypass some but not all defects in G protein regulated spore development.

Project description:Many cellular processes are modulated by cyclic AMP and nucleotide phosphodiesterases (PDEs) regulate this second messenger by catalyzing its breakdown. The major unique function of testicular Leydig cells is to produce testosterone in response to luteinizing hormone (LH). Treatment of Leydig cells with PDE inhibitors increases cAMP levels and the activity of its downstream effector, cAMP-dependent protein kinase (PKA), leading to a series of kinase-dependent signaling and transcription events that ultimately increase testosterone release. We have recently shown that PDE4B and PDE4C as well as PDE8A and PDE8B are expressed in rodent Leydig cells and that combined inhibition of PDE4 and PDE8 leads to dramatically increased steroid biosynthesis. Here we investigated the effect of PDE4 and PDE8 inhibition on the molecular mechanisms of cAMP actions in a mouse MA10 Leydig cell line model with SILAC mass spectrometry-based phosphoproteomics. We treated MA10 cells either with PDE4 family specific inhibitor (Rolipram) and PDE8 family specific inhibitor (PF-04957325) alone or in combination and quantified the resulting phosphorylation changes at five different time points between 0 and 180min. We identified 28,336 phosphosites from 4837 proteins and observed significant regulation of 749 sites in response to PDE4 and PDE8 inhibitor treatment. Of these, 132 phosphosites were consensus PKA sites. Our data strongly suggest that PDE4 and PDE8 inhibitors synergistically regulate phosphorylation of proteins required for many different cellular processes, including cell cycle progression, lipid and glucose metabolism, transcription, endocytosis and vesicle transport. Our data suggests that cAMP, PDE4 and PDE8 coordinate steroidogenesis by acting on not one rate-limiting step but rather multiple pathways. Moreover, the pools of cAMP controlled by these PDEs also coordinate many other metabolic processes that may be regulated to assure timely and sufficient testosterone secretion in response to LH.

Project description:BackgroundPost-traumatic stress disorder (PTSD) is the prevalent psychiatric disorder that induces alcohol use disorders (AUD) such as abnormal alcohol intake and anxiety. However, little is known about whether phosphodiesterase 2 (PDE2)-cAMP/cGMP signaling is involved in PTSD-induced AUD.MethodsThe present study used single-prolonged stress (SPS) to mimic PTSD that induced increases in ethanol intake and preference (2-bottle choice test) and anxiety-like behavior (elevated-plus maze test and novelty suppressed feeding test). PDE2 inhibitor Bay 60-7550 (Bay) was administered to the mice and protein kinase A (PKA) inhibitor H89 and PKG inhibitor KT5823 were micro-injected into dorsolateral striatum (DLS) and central amygdala (CA) of mice to determine whether the effects of Bay on anxiety-like behavior in SPS mice are brain region dependent.ResultsPDE2 inhibitor Bay rescued SPS-induced decreases in open arm entries and open arm time exposure in elevated-plus maze test and reversed increased latency to feed in the novelty suppressed feeding test. Moreover, SPS-induced ethanol use disorder was reversed by Bay as evidenced by decreased ethanol intake and preference without changing total fluid intake in the SPS mice after treatment with Bay. However, Bay did not change the ethanol metabolism or sucrose or quinine intake and preference. The locomotor activity was not affected after treatment with Bay. Interestingly, microinjection of PKA or PKG inhibitor H89 or KT5823 into DLS prevented the effects of Bay on alcohol intake and preference and cAMP-response element binding proteins phosphorylation and brain derived neurotrophic factor expression in DLS but not on the anxiety-like behavior in SPS mice. Microinjection of these inhibitors into CA prevented Bay-induced anxiolytic-like effects and cAMP-response element binding proteins phosphorylation and brain derived neurotrophic factor levels in CA but did not affect ethanol intake in SPS mice, indicating that the effects of Bay on different behaviors are brain region dependent.ConclusionsThese findings support the hypothesis that PDE2-cAMP/cGMP signaling may differentially mediate PTSD-induced AUD and anxiety-like behavior.

Dataset Information

A cAMP signaling model explains the benefit of maintaining two forms of phosphodiesterase in Dictyostelium.

Publications

A cAMP signaling model explains the benefit of maintaining two forms of phosphodiesterase in Dictyostelium.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets