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PubMed1992

Insulin desensitized beta 1-adrenergic receptor-mediated stimulation of adenylyl cyclase in SK-N-MC cells.

Receptor cross-talk is an emerging field which investigates cross-regulation between distinct classes of receptors. In the present work, we investigated the influence of activating the insulin receptor, a tyrosine kinase receptor, on beta-agonist activation of adenylyl cyclase, which is mediated by a G protein-linked receptor. Treatment of SK-N-MC neuroepithelioma cells with insulin generated a marked attenuation of beta 1-adrenergic receptor-mediated stimulation of adenylyl cyclase. This effect required nanomolar concentrations of insulin, occurred within minutes of exposure of these cells to insulin, and did not result from down-regulation of beta-adrenergic receptors. Insulin alone reduced the maximal isoproterenol-mediated stimulation of adenylyl cyclase by 50%, while the co-addition of the phosphatase inhibitor sodium vanadate increased the magnitude of insulin inhibition to 90%. Insulin provides an additional avenue for heterologous desensitization of beta-adrenergic receptors and their transmembranal signalling pathway.

Adenylyl Cyclases↗

PubMed1992

A pathway for luteinizing hormone releasing-hormone self-potentiation: cross-talk with the progesterone receptor.

This study investigates the signaling pathways that lead to acute augmentation of secretagogue-induced LH secretion, the physiologically relevant manifestation of which is LHRH self-potentiation. The consequence of LHRH self-potentiation is an augmented LH secretory response to subsequent exposure to the peptide. Although the mechanism for LHRH self-potentiation remains obscure, the second messenger cAMP and the steroid hormone progesterone share common characteristics in their acute augmentation of secretagogue-induced pituitary LH secretion, suggesting that cross-talk between the peptide and steroid hormone pathways may occur. The progesterone receptor would represent a point of convergence of several effectors known to augment secretagogue-induced LH secretion. In rat anterior pituitary cells cultured in the absence of progesterone, it was found that the progesterone receptor antagonist RU486 (2 nM) inhibits LHRH self-potentiation induced by hourly pulses of 1 nM LHRH. In the absence of added progesterone, RU486 also suppresses the augmentation of LHRH-stimulated LH secretion which is a consequence of increasing [cAMP]i with either 8-bromo-cAMP (1 mM) or forskolin (1 microM) treatment. The extent of the suppression of the cAMP action in the presence of RU486 is similar to that found with the RNA synthesis inhibitor, actinomycin D. The data are consistent with the hypothesis that a LHRH-stimulated protein kinase A cascade acts, in part, through transcriptional activation of the progesterone receptor. It is concluded that the mechanism of LHRH self-potentiation requires cross-talk with the progesterone receptor.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1992

Endotoxin transduces Ca2+ signaling via platelet-activating factor receptor.

Lipopolysaccharide (LPS) is a pathogenic substance causing severe multiple organ failures and high mortality. Although several LPS binding proteins have been identified, the molecular mechanism underlying the LPS signaling pathway still remains obscure. We have found that the LPS-induced Ca2+ increase in platelets and platelet aggregation is blocked by selective platelet-activating factor (PAF) receptor antagonists, thus suggesting a cross-talk between LPS and the PAF receptor. Next, we confirmed this hypothesis using the cloned PAF receptors [(1991) Nature 349, 342-346; (1991) J. Biol. Chem. 266, 20400-20405] expressed in Xenopus oocytes and Chinese hamster ovary (CHO) cells. In both systems, cells responded to LPS only when PAF receptors were expressed, and specific PAF binding was successfully displaced and reversibly dissociated by LPS. PAF receptor activation by LPS may represent a novel important pathway in the pathogenesis of circulatory collapse and systemic thrombosis caused by endotoxin.

Animals↗

PubMed1992

Cross-talk between M2 muscarinic and D1 dopamine receptors in the cat adrenal medulla.

In the study reported here we have reached two conclusions. First, the cat adrenal medulla chromaffin cell possesses a dopamine D1 receptor that seems to be coupled to an adenylyl cyclase. Second, this receptor regulates the muscarinic-mediated catecholamine release response through a negative feed-back loop which uses cyclic AMP as a second messenger. These conclusions are supported by the following findings: (i) SKF38393 (a selective D1 receptor agonist), but not quinpirole (a selective D2 agonist), inhibits the methacholine-mediated catecholamine release responses in a concentration-dependent manner (IC50 of around 1-2 microM). (ii) SCH23390 (a selective D1 antagonist), but not sulpiride (a selective D2 antagonist), reversed by 70% the inhibitory effects of SKF38393. (iii) Dibutyril cyclic AMP (500 microM) inhibited by 80% the secretory effects of methacholine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Cross-talk between tyrosine kinase and G-protein-linked receptors. Phosphorylation of beta 2-adrenergic receptors in response to insulin.

Protein kinases play a pivotal role in the propagation and modulation of transmembrane signaling pathways. Two major classes of receptors, G-protein-linked and tyrosine kinase receptors not only propagate signals but also are substrates for phosphorylation in response to stimulation by agonist ligands. Insulin (operating via tyrosine kinase receptors) and catecholamines (operating by G-protein-linked receptors) are counterregulatory with respect to lipid and carbohydrate metabolism. How, on a cellular level, these two distinct classes of receptors may cross-regulate each other remains controversial. In the present work we identify a novel cross-talk between members of two distinct classes of receptors, tyrosine kinase (insulin) and G-protein-linked (beta-adrenergic) receptors. Treatment of DDT1 MF-2 hamster vas deferens smooth muscle cells with insulin promoted a marked attenuation (desensitization) of beta-adrenergic receptor-mediated activation of adenylylcyclase. Measured by immune precipitation of beta 2-adrenergic receptors from cells metabolically labeled with [32P]orthophosphate, the basal state of receptor phosphorylation was increased 2-fold by insulin. Phosphoamino acid analysis revealed that for insulin-stimulated cells, the beta 2-adrenergic receptors showed increased phosphorylation on tyrosyl and decreased phosphorylation on threonyl residues. Phosphorylation of the beta-adrenergic receptor was rapid and peaked at 30 min following stimulation of cells by insulin. beta-Adrenergic receptor phosphorylation and attenuation of catecholamine-sensitive adenylylcyclase provide a biochemical basis for the counterregulatory effects of insulin upon catecholamine action.

Animals↗

PubMed1992

Enkephalin induces Ca2+ mobilization in single cells of bradykinin-sensitized differentiated neuroblastoma hybridoma (NG108-15) cells.

A study of the intracellular Ca2+ ([Ca2+]i) response of differentiated neuroblastoma x glioma hybrid cells (NG108-15 cell) to enkephalin (EK) was carried out by fura-2 video-imaging. EK alone did not influence [Ca2+]i in single cells. The opioid did, however, induce a marked [Ca2+]i rise, when the cells were incubated with bradykinin (BK) prior to the EK treatment. Such BK-assisted stimulation of the differentiated hybridoma cells by EK was completely abolished by pertussis toxin treatment. These results suggest that in single NG108-15 cells, EK induces Ca2+ mobilization which is assisted by cross-talk between the EK and BK receptor systems via a pertussis toxin-sensitive G protein.

Animals↗

PubMed1992

Signal transduction in mesangial cells.

Phenotype, growth, and functional characteristics of glomerular mesangial "myofibroblasts" are under the control of multiple hormones, vasoactive agents, autacoids, and cytokines. Several parallel signal transduction pathways couple receptor occupancy with functional changes, including phospholipases C, A2, and D breakdown of membrane phospholipids, and adenylate/guanylate cyclase activation. Changes of cytosolic ion concentrations, cyclic nucleotide accumulation, and eicosanoid biosynthesis are currently interpreted as intracellular signals for protein kinase activation. Phosphorylation of multiple substrates by serine/threonine kinases C, A, and G or by tyrosine kinases directly coupled to receptors, is a final step in cell activation. Cross-talk between signal transduction pathways, along with the release of eicosanoids and cytokines acting as intercellular mediators, provides the potential for interactive regulation of glomerular cell functions.

Adenylyl Cyclases↗

PubMed1992

Cross-talk between excitatory and inhibitory amino acids in the regulation of luteinizing hormone-releasing hormone secretion.

Inhibitory (IAA) and excitatory amino acid (EAA) neurotransmitters appear to play an important role in regulating reproductive functions. L-Glutamic acid (GLU), the major representative of the EAA system, stimulates LHRH release from arcuate nucleus-median eminence (AN-ME) fragments in vitro. Several studies have provided evidence for considering gamma-aminobutyric acid (GABA), a major IAA neurotransmitter, as another regulator of LHRH secretion. Recent reports have indicated that a cross-talk between GABA and GLU participates in the regulation of synaptic transmission in the brain. In concert with this notion, we present evidence indicating that this cross-talk between GABA and GLU appears to be also involved in neuroendocrinological paradigms. In this respect, bicuculline, a GABA-A receptor antagonist, blocked GLU-evoked LHRH secretion from AN-ME fragments in vitro without affecting basal LHRH release. In addition, activation of GABA-A receptors by muscimol (MUS) stimulated basal LHRH secretion. Interestingly, when MUS and GLU were added together to the incubation medium, an additive, stimulatory effect was observed. These observations clearly indicate that a GABAergic mechanism participates, via GABA-A receptors, in GLU-induced LHRH secretion from terminals of the ME. Furthermore, GABA-B receptors appear to negatively modulate the effects of GLU. Activation of GABA-B receptors by baclofen (BAC) blocked GLU-induced LHRH secretion, while phaclofen, a GABA-B receptor antagonist, reversed this effect. In summary, our data provide evidence for a cross-talk between EAA and IAA systems in the regulation of LHRH release, and, therefore, in the control of gonadal function.

Animals↗

PubMed1992

Regulation of formyl peptide receptor expression and its mRNA levels during differentiation of HL-60 cells.

When incubated with N6-2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP), HL-60 cells expressed formyl peptide receptor (FPR) (as assessed by ligand binding) and FPR transcripts in a time- and concentration-dependent fashion. Experiments using dbcAMP analogs modified at either the C-6 or C-8 position indicated that the process was mediated by a protein kinase A type I, and protein kinase A type I activity was isolated from undifferentiated HL-60 cells by DEAE-Sephacel chromatography. Forskolin mimicked the effects of dbcAMP. Forskolin and dbcAMP-dependent expression of FPR and FPR transcript was inhibited by staurosporine. Retinoic acid (but not retinal or retinol) was capable of inhibiting dbcAMP-dependent expression of FPR mRNA half-life. Dexamethasone enhanced the effects of dbcAMP and blocked the inhibitory effect of retinoic acid on expression of FPR and FPR transcripts. Phorbol 12-myristate 13-acetate (PMA) alone (1.5-15 nM) failed to induce HL-60 to express FPR and FPR transcripts. Low concentrations (1.5 nM) of PMA enhanced the ability of dbcAMP to induce HL-60 cells to express FPR and FPR transcript, whereas high (15 nM) concentrations of PMA inhibited dbcAMP effects. These results indicate that expression of FPR and FPR transcripts by HL-60 cells can be up- and down-regulated by agents that induce HL-60 cells to differentiate and that a "cross-talk" effect exists between protein kinase A and protein kinase C that modulates FPR gene transcription (and receptor expression) by these cells.

Alkaloids↗

PubMed2026

GPER and EGFR cross-talk highlight aldosterone- and MR antagonist-induced NO production in cultured endothelial cells.

INTRODUCTION: Aldosterone induces rapid, non-genomic vasodilation of the rat mesenteric vasculature, and mineralocorticoid receptor (MR) antagonists are widely used in cardiovascular disease, yet their pharmacological profiles beyond classical MR blockade remain unclear. We examined whether the G protein-coupled estrogen receptor (GPER/GPR30), functionally coupled to the epidermal growth factor receptor (EGFR), accounts for the rapid endothelial nitric oxide (NO) component of aldosterone action, and whether MR antagonists display intrinsic GPER-linked activity. METHODS: Aldosterone-induced vasodilation was assessed in isolated perfused rat mesenteric arterial beds precontracted with noradrenaline, and NO production was quantified in primary mesenteric endothelial cell cultures by DAF-FM fluorescence with validated vehicle controls. The mechanisms engaged by spironolactone, eplerenone and finerenone were interrogated with selective pharmacological tools and by endothelium removal. Ligand recognition was explored by molecular docking in a comparative model of the rat GPER built on the human GPER cryo-EM template. RESULTS: Aldosterone elicited concentration-dependent endothelial NO production (EC50 = 2.26 ± 0.3 nM) and vasodilation (EC50 = 0.9 ± 0.2 nM) that were closely correlated (R2 = 0.969, p < 0.01). All three MR antagonists blocked the aldosterone responses, yet each also evoked intrinsic, concentration-dependent NO production in the absence of aldosterone, eplerenone and spironolactone showing greater intrinsic efficacy than finerenone. Pretreatment with 100 nM of the GPER antagonist G-36 or 100 nM AG-1478 significantly reduced both aldosterone-induced DAF-NO signaling and vasodilation, whereas endothelium removal or L-NAME converted vasodilation into vasoconstriction. Aldosterone signaling additionally required PI3K, PKA and IP3 receptor-gated Ca2+ mobilization. Docking identified plausible receptor-engaging poses, with steroidal ligands converging on a shared cavity and finerenone adopting a distinct binding mode. DISCUSSION: MR antagonists elicit endothelial NO production through a G-36-sensitive, GPER-linked pathway functionally coupled to EGFR signaling, rather than acting as pure competitive antagonists in this context. Because recent cryo-EM work reveals a non-canonical extracellular GPER architecture, the docking results are interpreted as structurally plausible interaction scenarios rather than definitive orthosteric assignments; whether the behaviour reflects direct partial agonism at GPER or an indirect, GPER-dependent mechanism remains to be established by direct-binding studies. These findings expand current understanding of MR antagonist pharmacology.

GPER/GPR30↗

PubMed1992

Inhibition of insulin-like growth factor-I responses in MCF-7 cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds.

Insulin-like growth factor-I (IGF-I) stimulated the growth and [3H]thymidine uptake in MCF-7 human breast cancer cells grown in serum- and growth factor-inactivated serum-containing media. Cotreatment of the cells with IGF-I plus 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in a significant decrease in mitogen-induced cell proliferation and [3H]thymidine uptake. Similar effects were observed for cells treated with 2,3,7,8-TCDD and IGF-I plus 17 beta-estradiol. The relative antimitogenic activities of 2,3,7,8-TCDD and related compounds followed the order 2,3,7,8-TCDD greater than 2,3,7,8-tetrachlorodibenzofuran (TCDF) greater than 1,2,7,8-TCDF greater than 1,3,7,8-TCDD which was similar to their aryl hydrocarbon (Ah) receptor binding affinities. The results showed that 2,3,7,8-TCDD did not alter the IGF-I receptor mRNA levels or the KD values for binding of [125I]IGF-I to the IGF-I receptor in MCF-7 cells. However, 2,3,7,8-TCDD significantly decreased the number of IGF-I-induced IGF-I receptor binding sites and this may play a role in the growth-inhibitory properties of 2,3,7,8-TCDD and related compounds and in the 'cross-talk' between the two endocrine-response pathways.

Benzofurans↗

PubMed2025

Thyroid Hormone Action by Genomic and Nongenomic Molecular Mechanisms.

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are pivotal in regulating various physiological processes including growth, development, and metabolism. The biological actions of thyroid hormones are primarily initiated by binding to nuclear thyroid hormone receptors (TRs). These receptors, belonging to the superfamily of nuclear receptors, act as ligand-dependent transcription factors. Transcriptional regulation by TRs is mediated by the recruitment of coregulators, governing activation and repression of target genes, thereby modulating cellular responses to thyroid hormones. Beyond this canonical genomic pathway, TH can regulate the expression of genes not directly bound by TRs through cross-talk mechanisms with other transcription factors and signaling pathways. Thyroid hormones can also elicit rapid non-genomic effects, potentially mediated by extranuclear TR proteins or by interactions with membrane receptors such as integrin αvβ3. This non-genomic mode of action adds another layer of complexity to the diverse array of physiological responses orchestrated by thyroid hormones, expanding our understanding of their multifaceted actions.

Animals↗

PubMed1992

Capillary as a communicating medium in the microvasculature.

The preceding study (Dietrich and Tyml, 1992. Microvasc. Res. 43) demonstrated that a local application of norepinephrine (NE) on a capillary in a skeletal muscle produces a temporary reduction in blood flow within this capillary. The reduction is mediated via constriction of the supplying arteriole. The objective of the present study was to address the mechanism by which the local NE stimulus is propagated from the capillary to the arteriole. Using intravital video microscopy we measured red blood cell velocity in capillaries, and diameter of supplying arterioles, in the sartorius muscle in anesthetized frogs. Velocity responses were measured following iontophoretic application of NE (3 mM in the pipette) on the capillary, with or without pretreatment with 0.9 mM tetrodotoxin (nerve-specific sodium channel blocker), 30 mM lidocaine (nonspecific sodium channel blocker), and 30 mM yohimbine (alpha 2-receptor blocker). Diameter responses were measured before and after capillary damage introduced by microcautery. Tetrodotoxin did not block the NE-induced velocity reduction (i.e., from 0.2 to 0.07 mm/sec), while lidocaine attenuated it. Yohimbine blocked it only when applied on the same site as NE. Capillary damage abolished the NE-induced arteriolar constriction (i.e., from 27.8 to 21.5 microns). We conclude that the observed responses were not due to (1) direct diffusion of NE from the capillary to the arteriole, (2) conduction along adrenergic nerves, or (3) venous-arteriolar diffusional cross-talk. We interpret our data to indicate that the capillary itself could function as a communicating medium.

Animals↗

PubMed1992

Effects of isoproterenol and forskolin on carbachol- and fluoroaluminate-induced polyphosphoinositide hydrolysis, inositol trisphosphate production, and contraction in bovine iris sphincter smooth muscle: interaction between cAMP and IP3 second messenger systems.

We have investigated the effects of isoproterenol (ISO) and forskolin on carbachol(CCh)- and fluoroaluminate (AlF4-)-induced phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, myo-inositol 1,4,5-trisphosphate (IP3) production, 1,2-diacylglycerol, measured as phosphatidic acid (PA) formation, and contraction in the bovine iris sphincter smooth muscle. The data from these studies can be summarized as follows. (1) CCh (20 microM) stimulated significantly PIP2 hydrolysis, IP3 production, PA formation, and contraction. (2) Addition of ISO (0.1-25 microM), which raises the tissue cAMP level, to muscle precontracted with CCh attenuated PIP2 hydrolysis, IP3 production, PA formation and contraction in a time- and dose-dependent manner. (3) AlF4- (10 microM) induced a slow but progressive hydrolysis of PIP2, accompanied by parallel production of IP3, formation of PA, and contraction of the smooth muscle. The effects of AlF4- were dose-dependent and inhibited by deferoxamine, an Al3+ ion chelator. (4) Both forskolin (1-25 microM), which directly stimulates adenylate cyclase, and ISO inhibited the responses induced by AlF4- (10 microM) in a dose-dependent manner. (5) NaF (1-5 mM) had no effect on the activity of phospholipase C (PLC), purified from bovine iris sphincter. Furthermore, phosphorylation of the enzyme by catalytic subunit of protein kinase A had no inhibitory effect on PLC activity against PIP2. In conclusion, neither the muscarinic receptor nor PLC are the target sites for cAMP inhibition; instead the putative G-protein, which couples the activated muscarinic receptor to PLC, may be phosphorylated by cAMP-dependent protein kinase. This could attenuate the stimulation of PLC by the G-protein, thus resulting in inhibition of PIP2 hydrolysis and consequently leading to muscle relaxation. These results demonstrate cross-talk between the cAMP and IP3-Ca2+ second messenger systems and suggest that this could constitute a regulatory mechanism for the process of contraction-relaxation in smooth muscle.

Aluminum↗

PubMed1992

Cross-talk between cAMP and formylmet-leu-phe in human neutrophils: phosphorylation of a 52,000 molecular weight protein.

The mechanism of inhibition of neutrophil phagocytic functions by cAMP-elevating agents has not yet been clarified. In the present work, the effects of adenylate cyclase agonists on protein phosphorylation in the formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated human neutrophils were studied. Before stimulation, 32Pi-labelled cells were incubated with adenosine deaminase to remove the endogenously produced adenosine, an adenylate cyclase agonist itself. A protein of about 52,000 molecular weight was rapidly and transiently phosphorylated when neutrophils were stimulated with fMLP in the presence of isoproterenol, prostaglandin E1, histamine or 2-chloroadenosine. This phosphorylation was blocked by the antagonists of the receptors for the above-listed agents. No phosphorylation of the 52,000 molecular weight protein could be observed if either fMLP or the cAMP-elevating agent were applied alone. A calcium ionophore A23187 and dibutyryl-cAMP could replace fMLP and a cAMP-elevating agent, respectively. Phosphorylation of the 52,000 molecular weight protein was also demonstrated in cell lysates in the presence of cAMP, and in membrane preparations in the presence of the catalytic subunit of cAMP-dependent protein kinase. These data suggest that phosphorylation of the 52,000 molecular weight protein in intact cells is dependent on the cross-talk between the fMLP- and the cAMP-signalling pathways, and may thus be involved in the cAMP-regulatory mechanism.

Bucladesine↗

PubMed1992

Cross-talk regulation between cyclic AMP production and phosphoinositide hydrolysis induced by prostaglandin E2 in osteoblast-like cells.

In cloned osteoblast-like MC3T3-E1 cells, PGE2 stimulated both cAMP accumulation and the formation of inositol trisphosphate (IP3) dose dependently. The cAMP accumulation showed the peak value at 5 min and decreased thereafter, whereas the IP3 formation reached a plateau almost within 10 min and sustained it up to 30 min. The effect of PGE2 on cAMP accumulation (EC50 was 80 nM) was more potent than that on IP3 formation (EC50 was 0.8 microM). 12-O-Tetradecanoyl-phorbol-13-acetate (TPA), a protein kinase C (PKC)-activating phorbol ester, reduced the PGE2-induced cAMP accumulation, whereas 4 alpha-phorbol 12,13-didecanoate, a PKC-nonactivating phorbol ester, had little effect on the cAMP accumulation. 1-Oleoyl-2-acetyl-glycerol, a specific activator for PKC, inhibited PGE2-induced cAMP accumulation. TPA had little effect on cAMP accumulation induced by forskolin or NaF, a GTP-binding protein activator. So, the effect of TPA is presumed to be exerted at the point between the PGE2 receptor and Gs. On the other hand, forskolin and dibutyryl cAMP had little effect on the IP3 formation stimulated by PGE2. H-7, a PKC inhibitor, enhanced the PGE2-induced cAMP accumulation in comparison with HA1004, a control for H-7. Our data suggest that PGE2 regulates cAMP production through self-induced activation of PKC. These results strongly suggest that there is an autoregulatory mechanism in PGE2 signaling, and PGE2 modulates osteoblast functions through a cross-talk interaction between cAMP production and phosphoinositide hydrolysis in osteoblast-like cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1992

Regulation of the cAMP signal transduction pathway by protein kinase C in rat submandibular cells.

Treatment of rat submandibular acinar cell extracts with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) caused the dose-dependent activation of protein kinase C (PKC), assessed by the phosphorylation of a novel and highly specific substrate. This effect was duplicated by a diacylglycerol, but not by the 4 alpha-phorbol ester 4 alpha-phorbol 12,13-didecanoate. The TPA elevation of PKC was blocked by the PKC inhibitors H-7 and sangivamycin. In intact cells, TPA caused the translocation of PKC from cytosol to membrane, consistent with its known mode of activation. The beta-adrenergic agonist, isoproterenol, stimulated cAMP levels which were significantly reduced by preactivation of PKC. This inhibitory PKC effect was reversed by H-7. When cAMP was stimulated at the post-receptor level, however, by forskolin, NaF or GTP[gamma S], PKC did not inhibit, but rather enhanced the cyclic nucleotide response. Since PKC phosphorylated an endogenous protein of 55 kDa, the size of the beta 1 receptor, these findings indicate that, as in other cell types, PKC can desensitize adenylate cyclase by direct phosphorylation of the beta receptor, but potentiate the cAMP response by a post-receptor mechanism. In mucin secretion studies in the model, TPA alone caused the cAMP-independent release of up to 44% total mucin, which was much less than additive with the isoproterenol response. When the cAMP-mucosecretory response was stimulated at the adenylate cyclase level by forskolin, however, the TPA + forskolin effects were additive. These findings on the modulation of cAMP by PKC indicate cross-talk regulation in the phosphoinositide-cAMP signal transduction pathways in submandibular acinar cells.

Animals↗

PubMed2026

Cross-Kingdom Siderophores: Biosynthesis, Ecology, and Biotechnological Applications.

Microbial siderophores are high-affinity iron-binding compounds which are produced by bacteria, fungi, and actinomycetes to obtain iron and survive and interact with different species in an iron-deficient environment. While the conventional research on siderophore systems deals mainly with the study within the same taxa, modern researchers have increased their inclination toward cross-kingdom integration of siderophore behavior and their impact on host-associated environments. This can be largely attributed to differences in biosynthetic gene clusters, receptor systems, and regulatory networks, which produce distinct genotype-to-phenotype results determining microbial cooperation and competition. Current advancements in genomic research, together with omics studies like transcriptomics, proteomics, and metabolomics, have created newer insights into how siderophores function. However, the present literature evidences multiple major gaps in multi-omics data because the link between genomes and metabolomes remains weak due to inconsistent regulatory data sets and failure in identifying producer-consumer relationships in polymicrobial systems. Additionally, major constraints like molecular instability, delivery system limitations, host toxicity, limitations in upscaling, and regulatory issues delimit the use of siderophores in medical treatment, agricultural practices, and environmental biotechnology. This review aims to bridge the existing knowledge about siderophore biochemistry, biosynthesis, ecological functions, and genetic regulation across kingdoms while integrating multi-omics outlook with translational considerations. Thus, by connecting molecular mechanisms with evolutionary cross-talk, this study aims to provide a system-level framework in the world of siderophore-mediated iron uptake and therefore shapes future directions in emerging fields of microbial engineering, precision therapies, and sustainable biotechnology.

Fur regulation↗