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At least 19 recordsLinked to original sources
PubMed1992

The phosphoinositide signaling system and hypertension.

The phosphoinositide signaling system is common to many vasoconstrictor agents and as such is influential in the regulation of blood pressure. Recently, there have been major advances in our understanding of these lipids and their metabolism. Characterization of the phospholipase C isozymes and protein kinase C isozymes involved in transmembrane signaling has progressed rapidly. The role of diacylglycerol kinase as a regulator of protein kinase C activity has been established, and phosphatidic acid has been recognized as a cellular messenger. Studies in the spontaneously hypertensive rat have shown abnormalities of phospholipase C that could result in enhanced activity and explain changes in sensitivity reported in rats with this disease. During agonist activation of inositol lipid hydrolysis, levels of inositol 1,4,5-trisphosphate and 1,2-diacylglycerol are elevated in spontaneously hypertensive rats compared with Wistar-Kyoto control rats. These changes are observed early, prior to blood pressure stabilization, and may be downregulated once hypertension is established. In addition, there is evidence for reduced diacylglycerol kinase activity and enhanced protein kinase C activity in the spontaneously hypertensive rat. These data provide evidence for hyperresponsiveness of the phosphoinositide signaling system in the developmental stages of hypertension. However, confirmatory experiments in nongenetic animal models of hypertension and in human tissues are needed to establish that this is not just a phenotypic phenomenon of the spontaneously hypertensive rat.

Animals↗
PubMed2025

Analysis of stress-induced small proteins in Escherichia coli reveals that YoaI mediates cross-talk between distinct signaling systems.

Bacterial small proteins (≤ 50 amino acids) are an emerging class of regulators that modulate the activity of signaling networks that enable bacterial adaptation to stress. The Escherichia coli genome encodes at least 150 small proteins, most of which are functionally uncharacterized. We identified and characterized 17 small proteins induced in E. coli during magnesium (Mg2+) starvation using ribosome profiling, RNA sequencing, and transcriptional reporter assays. Several of these were transcriptionally activated by the PhoQ-PhoP two-component signaling system, which is crucial for Mg2+ homeostasis. Deletion or overexpression of some of these small proteins led to growth defects and changes in cell size under low-Mg2+ conditions, indicating physiological roles in stress adaptation. The small transmembrane protein YoaI, which was transcriptionally induced by the phosphate-responsive PhoR-PhoB signaling pathway, increased in abundance under Mg2+ limitation independently of yoaI transcription or PhoQ-PhoP signaling. YoaI activated a third signaling system, EnvZ-OmpR, which mediates responses to osmotic stress. Overall, this study establishes an initial framework for understanding how small proteins contribute to bacterial stress adaptation by facilitating cross-talk between different signaling systems. Our results suggest these proteins play broader roles in coordinating stress responses, reflecting the interconnected nature of cellular stress networks rather than strictly compartmentalized pathways responding to specific stressors.

Journal Article↗
PubMed1992

Intracellular signalling systems controlling the 5 alpha-reductase in glial cell cultures.

Glial cells are able to metabolize testosterone into DHT through the action of the enzyme 5 alpha-reductase. DHT may be further processed to 3 alpha-diol by the 3 alpha-hydroxysteroid-dehydrogenase. The aim of this study was to analyze if a modulation of two second messenger systems might be able to modify the 5 alpha-reductase and the 3 alpha-hydroxysteroid-dehydrogenase activities present in glial cells. To this purpose, the formation of DHT has been measured in rat glial cell cultures after different time of exposure to TPA, 4 alpha-Ph, an active and an inactive phorbol ester respectively, and 8-Br-cAMP. The results obtained indicate that the formation of DHT is not modified by the addition of phorbol esters. On the contrary, a statistically significant increase of 5 alpha-reductase activity, over control levels, has been observed after 6, 12, and 24 h of incubation with 8-Br-cAMP (10(-3) M). The effect of the cAMP analogue appears to be specific for the 5 alpha-reductase, since the 3 alpha-hydroxysteroid-dehydrogenase did not show any variation after exposure to the drug. In conclusion, the present data suggest that proteinkinase A (PKA) might be involved in the control of the 5 alpha-reductase in glial cells. It is postulated that nervous inputs utilizing cAMP as the second messenger might modify the activity of this enzyme in glial cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2025

The NmpRSTU multi-component signaling system of Myxococcus xanthus regulates expression of an oxygen utilization regulon.

UNLABELLED: Myxococcus xanthus has numerous two-component signaling systems (TCSs), many of which regulate the complex social behaviors of this soil bacterium. A subset of TCSs consists of NtrC-like response regulators (RRs) and their cognate histidine sensor kinases (SKs). We have previously demonstrated that a multi-component, phosphorelay TCS named NmpRSTU plays a role in M. xanthus social motility. NmpRSTU was discovered through a screen that identified mutations in nmp genes that restored Type-IV pili-dependent motility to a nonmotile strain. The Nmp pathway begins with the SK NmpU, which is predicted to be active in the presence of oxygen. NmpU phosphorylates another SK, NmpS, a hybrid kinase containing an RR domain and a HisKA-CA domain. These two kinases work in a reciprocal fashion: when NmpU is active, NmpS is inactive, and vice versa. Finally, the phosphorelay culminates in NmpS phosphorylating the NtrC-like RR NmpR. To better understand the role of NmpRSTU in M. xanthus physiology, we determined the NmpR regulon by combining in silico predictions of the NmpR consensus binding sequence with in vitro electromobility shift assays (EMSAs) and in vivo transcriptional reporters. We identified several NmpR-dependent, upregulated genes likely to be important in oxygen utilization. Additionally, we demonstrate NmpRSTU plays a role in fruiting body development, suggesting a role for oxygen sensing in this behavior. We propose that NmpRSTU senses oxygen-limiting conditions, and NmpR upregulates genes associated with optimal utilization of that oxygen. This may be necessary for M. xanthus physiology and behaviors in the highly dynamic soil where oxygen concentrations vary dramatically. IMPORTANCE: Bacteria use two-component signaling systems (TCSs) to respond to a multitude of environmental signals and subsequently regulate complex cellular physiology and behaviors. Myxococcus xanthus is a ubiquitous soil bacterium that encodes numerous two-component systems to respond to the conditions of its soil environment and coordinate multicellular behaviors such as coordinated motility, microbial predation, fruiting body development, and sporulation. To better understand how this bacterium uses a two-component system that has been linked to the sensing of oxygen concentrations, NmpRSTU, we determined the gene regulatory network of this system. We identified several genes regulated by NmpR that are likely important in oxygen utilization and for the M. xanthus response to varied oxygen concentrations in the dynamic soil environment.

Myxococcus xanthus↗
PubMed1992

Hormone signaling systems in inner medullary collecting ducts.

The inner medullary collecting duct is a complex tissue that exhibits a variety of hormone signaling systems. These include the following: adenylyl cyclase activity stimulated by vasopressin (AVP), beta-adrenergic agonists, or prostanoids and inhibited by alpha 2-adrenergic agents or adenosine; guanylate cyclase activity in response to atrial natriuretic peptide (ANP); phospholipase C activity stimulated by ANP, AVP, bradykinin, endothelin, epidermal growth factor (EGF), and muscarinic cholinergic agents; and phospholipase A2 activity stimulated by AVP, bradykinin, EGF, and endothelin. The signal transduction mechanisms for each of these hormone signaling systems is succinctly reviewed, and the interactions between different signaling pathways are discussed. Central to this interaction is the mutually inhibitory relationship between activation of adenylyl cyclase and phospholipases. Increasing cellular adenosine 3',5'-cyclic monophosphate content impairs activation of phospholipases A2 and C; conversely, stimulation of phospholipase C impairs AVP-stimulated adenylyl cyclase activity via activation of protein kinase C.

Adenylyl Cyclases↗
PubMed1992

Transcription of the Bacillus subtilis sacX and sacY genes, encoding regulators of sucrose metabolism, is both inducible by sucrose and controlled by the DegS-DegU signalling system.

The adjacent sacX and sacY genes are involved in sucrose induction of the Bacillus subtilis sacB gene by an antitermination mechanism. sacB, encoding the exoenzyme levansucrase, is also subject to regulation by the DegS-DegU signalling system. Using sacXY'-lacZ and sacX'-lacZ fusions, we show that the transcription of the sacX and sacY genes is both inducible by sucrose and regulated by DegU. sacX and sacY appear to constitute an operon, since the deletion of the sacX leader region abolished the expression of a sacXY'-lacZ fusion. The degU-dependent promoter was located by deletion analysis and reverse transcriptase mapping 300 nucleotides upstream from the sacX initiator codon. Sucrose induction of the sacX'-lacZ fusion requires either SacY or the homologous SacT antiterminator, which is involved in sucrose induction of the intracellular sucrase gene (sacPA operon). Sequence analysis of the sacX leader region revealed (20 nucleotides downstream from the transcription start site) a putative binding site for these regulators; however, no structure resembling a rho-independent terminator could be found overlapping this site, unlike the situation for sacPA and sacB. Deletion of a segment of the leader region located 100 nucleotides downstream from this site led to constitutive expression of the sacXY'-lacZ and sacX'-lacZ fusions. These results suggest that the mechanism of sucrose induction of sacXY is different from that of sacPA and sacB.

Bacillus subtilis↗
PubMed1992

Losartan inhibits the angiotensin II-induced stimulation of the phosphoinositide signalling system in vascular smooth muscle cells.

2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl-4-yl)methyl]imidazole, potassium salt (Losartan) (previous name, DuP 753 or MK 954) is a nonpeptide angiotensin II receptor antagonist. This study was performed to investigate the ability of Losartan to inhibit the angiotensin II-induced stimulation of the phospoinositide signalling system and the angiotensin II-induced hypertrophy in aortic vascular smooth muscle cells of normotensive Wistar-Kyoto rats. 10(-7) M Losartan abolished the angiotensin II-induced formation of inositol 1,4,5-trisphosphate in vascular smooth muscle cells. 10(-6) M Losartan completely abolished the angiotensin II-induced elevation of the intracellular free Ca2+ concentration ([Ca2+]i). 10(-6) M Losartan lacked effects on the [Arg8]vasopressin-induced elevation of [Ca2+]i. In addition, 10(-6) M completely inhibited the angiotensin II-induced stimulation of Na+/H+ exchange in the vascular smooth muscle cells. 10(-10) to 10(-6) M Losartan inhibited the angiotensin II-induced cell protein synthesis in a concentration-dependent manner, yielding to an effective concentration (ED50) of 6.2 +/- 1.8 x 10(-8) M (n = 4). Losartan did not affect the platelet-derived growth factor-BB-induced increase in cell protein. These results show that Losartan is a highly specific angiotensin II receptor antagonist which inhibits angiotensin II-induced cell growth and thus may have beneficial effects on the development and regression of vascular hypertrophy.

Angiotensin II↗
PubMed1992

Characterization of H2 histamine receptor: linkage to both adenylate cyclase and [Ca2+]i signaling systems.

We undertook these studies to examine the intracellular mechanisms of histamine action using a rat hepatoma-derived cell line that had been transfected to express the H2 histamine receptor cDNA. Transfected cells demonstrated increased adenosine 3',5'-cyclic monophosphate production, membrane inositol phospholipid turnover, and intracellular Ca2+ concentration ([Ca2+]i) in response to histamine. All of the effects could be inhibited with the H2 histamine receptor antagonist cimetidine, and the increased membrane inositol phospholipid turnover and [Ca2+]i were abolished by cholera toxin pretreatment of cells. These data support the notion that a single histamine H2 receptor can be linked to two stimulatory intracellular signaling systems.

Adenylyl Cyclases↗
PubMed1976

Receptor interactions in a signalling system: competition between ribose receptor and galactose receptor in the chemotaxis response.

Galactose and ribose receptors are shown to compete for a common site by comparing the specificities of the purified receptors with the specificity of the whole organism response. Ribose does not bind to the purified galactose receptor but inhibits the in vivo galactose response. A mutant lacking the ribose receptor shows no inhibition of the galactose response even at very high ribose concentrations. The results can be explained by a mechanism involving (a) a ligand-induced conformational change in the receptor which produces a combining site with affinity for the molecule that serves as a first component of the signalling system and (b) a limited number of such first component molecules that cannot bind both receptors simultaneously. The mechanism may have considerable generality for sensory, hormonal, and transport systems.

Allosteric Regulation↗
PubMed2026

Ecr positively regulates activity of the PhoQ/PhoP signalling system in Klebsiella pneumoniae.

BACKGROUND: The rising prevalence of polymyxin resistance in multidrug-resistant Klebsiella pneumoniae presents a critical situation with limited therapeutic options. METHODS: Methods Genomic sequencing of 15 clinical polymyxin-resistant K. pneumoniae strains with multidrug resistance revealed that MgrB inactivation, predominantly disrupted by insertion sequences (ISs) in the IS1, IS4, and IS5 families, was the leading cause of polymyxin resistance. Comparative transcriptomics of wild-type, ΔmgrB, and ΔmgrBΔphoP were performed to elucidate the MgrB-PhoPQ regulatory network. RESULTS: This study conducted a system-wide analysis of the regulatory network and identified a species-specific PhoPQ regulon in K. pneumoniae.Beyond the classical MgrB-PhoPQ-ArnBCADTEF pathway, we identified a previously unannotated PhoPQ-regulated gene, 144 bp LN739_RS09850, encoding an Ecr homologue from Enterobacter cloacae. This protein has been reported to confer colistin heteroresistance, with the underlying mechanism not yet functionally validated. This study revealed that overexpression of Ecr homologues decreased colistin susceptibility in both K. pneumoniae and E. cloacae, but this phenotype was abolished upon phoP deletion, confirming PhoP's essential role. Consistent with this dependency, comparative transcriptomics of Ecr-overexpressing K. pneumoniae vs. control revealed significant upregulation of mgrB, phoPQ, arnBCADTE, and pmrD. Two-hybrid bacterial assays further demonstrated direct Ecr-PhoQ interaction. Electrophoretic mobility shift assay confirmed that PhoP directly binds to the ecr promoter in vitro, and a β-galactosidase reporter assay demonstrated that PhoP enhanced ecr promoter activity, indicating that PhoP regulates ecr expression by directly controlling its transcription. CONCLUSION: Collectively, these findings suggest that PhoP may directly activate the transcription of Ecr, with Ecr feedback activating the PhoPQ system via interaction with PhoQ, leading to induction of the arn operon and consequent polymyxin resistance.

Klebsiella pneumoniae↗
PubMed1992

Volume-dependent regulation of sodium and potassium fluxes in cultured vascular smooth muscle cells: dependence on medium osmolality and regulation by signalling systems.

To identify ion transport systems involved in the maintenance of vascular smooth muscle cell volume the effects of incubation medium osmolality and ion transport inhibitors on the volume and 86Rb and 22Na transport in cultured smooth muscle cells from rat aorta (VSMC) have been studied. A decrease of medium osmolality from 605 to 180 mosm increased intracellular water volume from 0.6 to 1.3 microliters per 10(6) cells. Under isosmotic conditions, cell volume was decreased by ouabain (by 10%, P less than 0.005) but was not influenced by bumetanide, furosemide, EIPA and quinidine. These latter compounds were also ineffective in cell volume regulation under hypotonic buffer conditions. Under hyperosmotic conditions, cell volume was decreased by bumetanide (by approximately 7%, P less than 0.05) and by ethylisopropyl amiloride (by approximately 13%, P less than 0.005). Ouabain-sensitive 86Rb influx was decreased by 30-40% under hypoosmotic conditions. An increase in medium osmolality from 275 to 410 mosm resulted in an approximately eightfold increase in bumetanide-inhibited 86Rb influx and 86Rb efflux. The (ouabain and bumetanide)-insensitive component of 86Rb influx was not dependent on the osmolality of the incubation medium. However (ouabain and bumetanide)-insensitive 86Rb efflux was increased by approximately 1.5-2 fold in VSMC incubated in hypotonic medium. Ethylisopropyl amiloride-inhibited 22Na influx was increased by approximately sixfold following osmotic-shrinkage of VSMC. The data show that both Na+/H+ exchange and Na+/K+/2Cl- cotransport may play a major role in the regulatory volume increase in VSMC. Basal and shrinkage-induced activities of Na+/K+/2Cl- cotransport in VSMC were similarly sensitive to inhibition by either staurosporin, forskolin, R24571 or 2-nitro-4-carboxyphenyl N,N-diphenylcarbomate (NCDC). In contrast basal and shrinkage-induced Na+/K+/2Cl- cotransport were differentially inhibited by NaF (by 30 and 65%, respectively), suggesting an involvement of guanine nucleotide binding proteins in the volume-sensitive activity of this carrier. Neither staurosporin, forskolin, R24571 nor NCDC influenced shrinkage-induced Na+/H+ exchange activity. NaF increased Na+/H+ exchanger activity under both isosmotic and hyperosmotic conditions. These data demonstrate that different intracellular signalling mechanisms are involved in the volume-dependent activation of the Na+/K+/2Cl- cotransporter and the Na+/H+ exchanger.

Alkaloids↗
PubMed1992

Impairment of glycosyl-phosphatidylinositol-dependent insulin signaling system in isolated rat hepatocytes by streptozotocin-induced diabetes.

The addition to different types of cells of an inositol-phosphate glycan, generated by the phospholipase C-catalyzed hydrolysis of a insulin-sensitive glycosyl-phosphatidylinositol (glycosyl-PI), mimics some of the biological effects of this hormone. Recently, a specific, time-, dose-, and energy-dependent transport system for this inositol-phosphate glycan has been identified in isolated rat hepatocytes. Here, we show that streptozotocin-induced diabetes mellitus reduced (by about 60%) the basal content of the insulin-sensitive glycosyl-PI in isolated rat hepatocytes. Moreover, streptozotocin-induced diabetes blocked the hydrolysis of the glycosyl-PI in response to insulin, diminished inositol phosphate-glycan uptake by the hepatocytes, and abolished the stimulatory effect of this compound on glycogen synthesis. All these metabolic changes caused by streptozotocin administration were reversed by treatment of the animals with insulin. Our results support the hypothesis that insulin resistance in streptozotocin-induced diabetic rats is related to the impairment of glycosyl-PI metabolism.

Animals↗
PubMed1992

Effect of electroconvulsive shock on 5-HT2 and alpha 1-adrenoceptors and phosphoinositide signalling system in rat brain.

We studied the effect of repeated administration of electroconvulsive shock (ECS) on alpha 1-adrenoceptor subtype (alpha 1A and alpha 1B) and 5-HT2 (serotonin-2) receptors and receptor-mediated phosphoinositide (PI) hydrolysis in rat cerebral cortex. We observed that repeated administration with ECS significantly increased the density of 5-HT2 receptors, as labeled by [3H]ketanserin, as well as 5-HT-stimulated [3H]inositol-1-phosphate ([3H]IP1) in rat cerebral cortex. We also observed that repeated ECS administration caused a significant increase in the number of alpha 1-adrenoceptors and the alpha 1B-adrenoceptor subtype as measured by (+/-)-beta-([125I]iodo-4-hydroxyphenyl)-ethyl-aminomethyl-tetralone binding. However, it had no significant effects on norepinephrine (NE)-stimulated [3H]IP1 formation or alpha 1A-adrenoceptor subtype. These results thus suggest that up-regulation of 5-HT2 receptors after administration with ECS is associated with increased 5-HT-stimulated [3H]IP1 formation. The lack of effects on NE-stimulated PI turnover in ECS treated rats may be due to its lack of effect on the alpha 1A-adrenoceptor subtype.

Animals↗