A current challenge in cellular signaling is to decipher the complex intracellular spatiotemporal organization that any given cell type has developed to discriminate among different external stimuli acting via a common signaling pathway. This obviously applies to cAMP and cGMP signaling in the heart, where these cyclic nucleotides determine the regulation of cardiac function by many hormones and neuromediators. Recent studies have identified cyclic nucleotide phosphodiesterases as key actors in limiting the spread of cAMP and cGMP, and in shaping and organizing intracellular signaling microdomains. With this new role, phosphodiesterases have been promoted from the rank of a housekeeping attendant to that of an executive officer.
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A propofol binding site in the voltage sensor domain mediates inhibition of HCN1 channel activity.
Sci Adv
January 2025
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Article Synopsis
- HCN ion channels play a key role in cellular activity and pain perception, with propofol acting as an analgesic by inhibiting their function.
- Researchers used a propofol analog to pinpoint binding sites on the human HCN1 isoform, revealing a specific pocket formed by certain residues in the channel.
- Mutations in this binding pocket affect propofol's ability to modulate HCN1 currents, highlighting its specific binding mechanism and offering insights for developing targeted HCN channel modulators.
[The mechanism of GSK-3β/CREB signaling pathway regulating macrophage pyroptosis and participating in the occurrence and development of diabetic foot ulcer].
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi
December 2024
Department of Endocrinology, The Fourth Hospital of Changsha(Changsha Hospital of Hunan Normal University), Changsha 410000, China.
Objective To investigate the role and possible mechanism of glycogen synthase kinase-3 beta (GSK-3β)/cAMP response element binding protein (CREB) signaling pathway in regulating macrophage pyroptosis in the pathogenesis and development of diabetic foot ulcer (DFU). Methods Thirty rats were randomly divided into control group, DFU group and GSK-3β inhibited group, with 10 rats in each group. Fasting blood glucose (FBG) was detected by dynamic blood glucose detector.
View Article and Find Full Text PDFInhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung.
Nat Commun
January 2025
Center for Infection and Immunity, Guangdong Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, Guangdong, China.
Suppression of chimeric antigen receptor-modified T (CAR-T) cells by the immunosuppressive tumor microenvironment remains a major barrier to their efficacy against solid tumors. To address this, we develop an anti-PD-L1-expressing nanovesicle loaded with the STING agonist cGAMP (aPD-L1 NVs@cGAMP) to remodel the tumor microenvironment and thereby enhance CAR-T cell activity. Following pulmonary delivery, the nanovesicles rapidly accumulate in the lung and selectively deliver STING agonists to PD-L1-overexpressing cells via the PD-1/PD-L1 interaction.
View Article and Find Full Text PDFExcitable Ras dynamics-based screens reveal RasGEFX is required for macropinocytosis and random cell migration.
Nat Commun
January 2025
Laboratory of Single Molecule Biology, Graduate School of Science and Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Excitable systems of eukaryotic chemotaxis can generate asymmetric signals of Ras-GTP-enriched domains spontaneously to drive random cell migration without guidance cues. However, the molecules responsible for the spontaneous signal generation remain elusive. Here, we characterized RasGEFs encoded in Dictyostelium discoideum by live-cell imaging of the spatiotemporal dynamics of Ras-GTP and hierarchical clustering, finding that RasGEFX is primarily required for the spontaneous generation of Ras-GTP-enriched domains and is essential for random migration in combination with RasGEFB/M/U in starved cells, and they are dispensable for chemotaxis to chemoattractant cAMP.
View Article and Find Full Text PDFA Penetrable AAV2 Capsid Variant for Efficient Intravitreal Gene Delivery to the Retina.
Invest Ophthalmol Vis Sci
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Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Purpose: This study aimed to identify a novel recombinant adeno-associated virus (rAAV) capsid variant that can widely transfect the deep retina through intravitreal injection and to assess their effectiveness and safety in gene delivery.
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