Functional Insights into Protein Kinase A (PKA) Signaling from C. elegans

Sadeghian, Fereshteh; Castaneda, Perla G.; Amin, Mustafi R.; Cram, Erin J.

doi:10.3390/life12111878

Cited by 4 publications

(3 citation statements)

References 124 publications

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“…KIN-1, the C. elegans ortholog of human PKA catalytic subunit has been reported to phosphorylate and stabilize ATGL-1 and activate lipolysis 16 . The PKA pathway responds to hormonal signals representing stresses, including starvation in both mammals and nematodes 75–77 . Our results confirm the crucial role of KIN-1 and SIR-2.1 and point out the possibility that while KIN-1/PKA pathway incorporates an organismal, neuroendocrine control into lipolysis regulation, SIR-2.1 responds to cellular changes in nutrient availability in the intestine which is in direct correlation with food availability in the gut lumen.…”

Section: Discussionmentioning

confidence: 99%

An intestinal Sir2-HSF1-ATGL1 pathway regulates lipolysis inC. elegans

Somogyvári,

Khatatneh,

Hajdú

et al. 2024

Preprint

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Proteostasis maintenance and lipid metabolism are critical for survival and promote longevity, however, their coordination is largely unclear. Here we show that the heat shock factor HSF-1 and the proteostasis state regulates lipolysis in C. elegans. We find that in response to starvation, the sirtuin 1 ortholog SIR-2.1 activates lipolysis by upregulation of the adipose triglyceride lipase ATGL-1. In feeding worms, intestinal HSF-1 represses ATGL-1 expression and lipolysis via the microRNA system. In starving worms, SIR-2.1 suspends a miR-53-mediated suppression of lipolysis by inhibiting its HSF-1-dependent expression. The apparent antagonism of SIR-2.1 and HSF-1, distinct from their synergism at heat shock promoters suggests a context-specific regulation of HSF-1 by SIR-2.1. We demonstrate that the SIR-2.1 and protein kinase A pathways are both indispensable, and independently converge on ATGL-1 for lipolysis. HSF-1 activation by proteostasis disturbances inhibits starvation-induced lipid mobilization, whereas its age-related decline limits fat deposition through atgl-1. Our findings reveal a crosstalk between proteostasis and lipid/energy metabolism, which may modulate stress resilience and aging.

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Section: Discussionmentioning

confidence: 99%

An intestinal Sir2-HSF1-ATGL1 pathway regulates lipolysis inC. elegans

Somogyvári,

Khatatneh,

Hajdú

et al. 2024

Preprint

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“…cAMP is a ubiquitous second messenger in eukaryotes and prokaryotes that plays a crucial role in intracellular signal transduction [ 30 ]. In eukaryotes, cAMP primarily activates protein kinase A (PKA) and the exchange protein activated by cAMP (Epac), which influence cellular processes like proliferation, differentiation, and apoptosis [ 31 , 32 , 33 ]. In this context, it was observed by in vitro assays that the excystation of G. lamblia cysts was significantly blocked when the PKA inhibitor, amide 14–22, was administered during the initial stages of excystation [ 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

Rosmarinic Acid Present in Lepechinia floribunda and Lepechinia meyenii as a Potent Inhibitor of the Adenylyl Cyclase gNC1 from Giardia lamblia

Zurita,

Vega Hissi,

Cianci Romero

et al. 2024

Plants

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Giardiasis is a parasitosis caused by Giardia lamblia with significant epidemiological and clinical importance due to its high prevalence and pathogenicity. The lack of optimal therapies for treating this parasite makes the development of new effective chemical entities an urgent need. In the search for new inhibitors of the adenylyl cyclase gNC1 obtained from G. lamblia, 14 extracts from Argentinian native plants were screened. Lepechinia floribunda and L. meyenii extracts exhibited the highest gNC1 inhibitory activity, with IC50 values of 9 and 31 µg/mL, respectively. In silico studies showed rosmarinic acid, a hydroxycinnamic acid present in both mentioned species, to be a promising anti-gNC1 compound. This result was confirmed experimentally, with rosmarinic acid showing an IC50 value of 10.1 µM. Theoretical and experimental findings elucidate the molecular-level mechanism of rosmarinic acid, pinpointing the key interactions stabilizing the compound–enzyme complex and the binding site. These results strongly support that rosmarinic acid is a promising scaffold for developing novel compounds with inhibitory activity against gNC1, which could serve as potential therapeutic agents to treat giardiasis.

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“…Therefore, it is critical to ensure the subcellular localization and optimal concentration of second messengers. For example, PKA can modulate the release of Ca 2+ by activating plasma membrane proteins, such as transient receptor potential (TRPV) channels (Sadeghian et al, 2022). In turn, Ca 2+ can directly influence PKA by regulating various isoforms of adenylyl cyclase (AC), including 1, 3, 5, 6, 8, and 9, thereby impacting cAMP production.…”

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confidence: 99%

Real‐Time FRET‐Based Measurements of Ca²⁺/PKA Dynamics in Plasma Membrane Microdomains of Primary Hippocampal Neurons

Sobolczyk‐Prawda,

Boczek

2024

Current Protocols

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Both Ca2+ and protein kinase A (PKA) are multifaceted and ubiquitous signaling molecules, essential for regulating the intricate network of signaling pathways. However, their dynamics within specialized membrane regions are still not well characterized. By using genetically encoded fluorescent indicators specifically targeted to distinct plasma membrane microdomains, we have established a protocol that permits observing Ca2+/PKA dynamics in discrete neuronal microdomains with high spatial and temporal resolution. The approach employs a fluorescence microscope with a sensitive camera and a dedicated CFP/YFP/mCherry filter set, enabling the simultaneous detection of donor‐acceptor emission and red fluorescence signal. In this detailed step‐by‐step guide, we outline the experimental procedure, including isolation of rat primary neurons and their transfection with biosensors targeted to lipid rafts or non‐raft regions of plasma membrane. We provide information on the necessary equipment and imaging setup required for recording, along with highlighting critical parameters and troubleshooting guidelines for real‐time measurements. Finally, we provide examples of the observed Ca2+ and PKA changes in specific cellular compartments. The application of this technique may have significant implications for studying cross‐talk between second messengers and their alterations in various pathological conditions. © 2024 Wiley Periodicals LLC.

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Functional Insights into Protein Kinase A (PKA) Signaling from C. elegans

Cited by 4 publications

References 124 publications

An intestinal Sir2-HSF1-ATGL1 pathway regulates lipolysis inC. elegans

An intestinal Sir2-HSF1-ATGL1 pathway regulates lipolysis inC. elegans

Rosmarinic Acid Present in Lepechinia floribunda and Lepechinia meyenii as a Potent Inhibitor of the Adenylyl Cyclase gNC1 from Giardia lamblia

Real‐Time FRET‐Based Measurements of Ca²⁺/PKA Dynamics in Plasma Membrane Microdomains of Primary Hippocampal Neurons

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Functional Insights into Protein Kinase A (PKA) Signaling from C. elegans

Cited by 4 publications

References 124 publications

An intestinal Sir2-HSF1-ATGL1 pathway regulates lipolysis inC. elegans

An intestinal Sir2-HSF1-ATGL1 pathway regulates lipolysis inC. elegans

Rosmarinic Acid Present in Lepechinia floribunda and Lepechinia meyenii as a Potent Inhibitor of the Adenylyl Cyclase gNC1 from Giardia lamblia

Real‐Time FRET‐Based Measurements of Ca2+/PKA Dynamics in Plasma Membrane Microdomains of Primary Hippocampal Neurons

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Real‐Time FRET‐Based Measurements of Ca²⁺/PKA Dynamics in Plasma Membrane Microdomains of Primary Hippocampal Neurons