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Results for “Receptor Cross-Talk”

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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↗

PubMed1991

Modulation of muscarinic receptor-mediated adenylate cyclase and phospholipase C responses in rat retina.

1. Agonist activation of rat retina muscarinic receptors results in suppression of cyclic AMP (cAMP) generation and enhanced phosphoinositide hydrolysis. 2. Pharmacological manipulations that elevate cAMP or stable analogues of cAMP attenuate the acetylcholine (ACh)-induced enhancement of phosphoinositide hydrolysis. We postulate that cross-talk between adenylate cyclase and phospholipase C signal transducing systems probably exists in rat retina, as has been described for other systems. 3. Intraocular administration of pertussis toxin attenuated the response of both adenylate cyclase and phospholipase C to muscarinic stimulation, suggesting that some retinal muscarinic receptors are apparently coupled to their effector systems via pertussis toxin sensitive G proteins.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1991

Antiparkinsonian dopamine agonists: a review of the pharmacokinetics and neuropharmacology in animals and humans.

With the intention of compensating for the deficit of endogenous dopamine (DA) in the basal ganglia of Parkinsonian patients by substitution with agents which directly stimulate central DA receptors, synthetic DA agonists have been introduced almost 20 years ago for the symptomatic treatment of Parkinson's disease. The original expectation that DA agonists would be able to completely restore extrapyramidal motor function in Parkinsonian patients has turned out as too mechanistic and simplicative. However, undoubtedly DA agonists have improved therapeutic possibilities in Parkinson's disease. Thus, clinical evidence from controlled chronic studies in patients indicates that the therapeutic results following the early application of DA agonists in combination with L-DOPA on a long-term base are superior to the respective monotherapy. However, none of the DA agonists currently employed for antiparkinsonian treatment i.e. apomorphine and the ergoline derivatives bromocriptine, lisuride and pergolide, is optimal with respect to pharmacokinetic properties (poor oral bioavailability with considerable intra- and interindividual variation) or pharmacological profiles (low selectivity for DA receptors in case of the ergot agonists). The pathophysiology underlying Parkinson's disease which turned out more complex than initially expected might provide another explanation for the limited therapeutic potential of DA agonists. Therefore, apart from summarizing the pharmacokinetics, biotransformation, neuropharmacology and neurobiochemistry of the DA agonists employed clinically, the present article also reviews physiological aspects of (a) central dopaminergic neurotransmission including the topographical distribution of DA receptor subtypes and their functional significance, (b) the intracellular signal processing in striatal output neurons and (c) the intraneuronal mechanisms which integrate the various neurotransmitter signals converging on the striatal output neuron to a demand-adjusted effector cell response via the cross-talk between the different second messenger systems. Based on these considerations, potential pharmacological approaches for the development of improved antiparkinsonian drugs are outlined. There is a therapeutic demand for more selective and better bioavailable DA agonists. In particular, selective D-1 receptor agonists are highly desirable to provide a more specific probe than SKF 38 393 for clarifying the current controversy on the disparate findings in nonprimate species and monkeys or Parkinsonian patients, respectively, regarding the functional significance of D-1 receptors for the antiparkinsonian action of DA agonists or L-DOPA. The therapeutic importance of D-2 receptor activation is generally accepted; whether DA agonists combining a balanced affinity to both D-1 and D-2 receptors within one molecule (to some extent a property of apomorphine) might be superior to subtype-specific DA agonists remains to be tested clinically.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Intracellular signaling in the gonads.

The regulation of steroidogenesis in both the ovary and testis involves a complex interaction of a diversity of hormones and intracellular signaling pathways. The recent cloning of LH and FSH receptors has paved the way for an increased understanding of the mechanisms of receptor conformation, ligand-receptor interaction, and facilitation of post-receptor activity. The dominant role played by LH in the regulation of steroid production appears to be mediated by more than one intracellular signaling pathway. In addition to the stimulation of the adenylate cyclase-cAMP pathway, also known to be stimulated by FSH, the actions of LH may be additionally mediated by other intracellular messengers, such as those derived from the PLC pathway. Steroidogenesis in the gonads appears to be modulated by a variety of factors in addition to the gonadotropins. In this review, those factors of intracellular signaling mechanisms of which we have some understanding have been discussed. These include GnRH, PGF2 alpha, Ang II, VIP, GHRH, TNF alpha, CRF, EGF, and TGF alpha. Many of these factors have been shown to be locally synthesized, and specific receptors have been identified in the gonads. Many gonadal factors have the capacity to exert effects on steroidogenesis independent of the gonadotropins. Alternately, they have been demonstrated to alter the gonadal response to the gonadotropins via autocrine, paracrine, and intracrine mechanisms. As yet, our understanding of the intracellular signaling mechanisms used by novel gonadal regulators is limited. The involvement of the PLC, PLA2, and PLD pathways in this regard has been reviewed. It is becoming apparent that multiple signaling pathways may be stimulated by a single hormone, as in the case of GnRH, PGF2 alpha, and LH. The complexity of intracellular signal transduction in the gonads is enhanced by the potential cross-talk at numerous steps in the signaling cascades.

Adenylyl Cyclases↗

PubMed1991

Modulation of the B cell response to T-independent antigens by prostaglandins: evidence for effector system cross-talk.

The extracellular environment is a major factor in determining the responsiveness of a cell to particular stimuli. For example, E series prostaglandins suppress B cell responses to T-independent antigens, mitogen stimulation of DNA synthesis and proliferation, and the primary immune response. We investigated the effects of prostaglandins on the intracellular signals generated by receptor-coupled effector systems in B lymphocytes. Pretreating splenocytes from athymic nude mice with forskolin, PGE1, or PGE2 decreased the magnitude of anti-IgM-induced changes in cytosolic free [Ca2+]. Addition of 8-Br-cAMP, forskolin, PGE1, or PGE2 following stimulation with anti-IgM resulted in a decrease in the intracellular calcium signal measured by fluorescence-activated cell sorting using Indo-1 as a Ca2+ indicator. This decrease was not a result of an inhibition of influx across the plasma membrane. Thus activation of adenylate cyclase by prostaglandins modifies the generation of signals by phosphoinositidase C. This effector system cross-talk between adenylate cyclase and phosphoinositidase C is consistent with and may account for the inhibitory effects of prostaglandins in B cell responses.

8-Bromo Cyclic Adenosine Monophosphate↗

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

Steroids and growth promoting factors in the regulation of expression of genes and gene networks.

Steroid hormones and growth promoting factors regulate the expression of a number of genes involved in cellular growth and differentiation. In many cases, cellular proliferation and differentiation-specific pathways are mutually exclusive. As an example for the mechanism of mutual exclusion, transcription factors responsible for pathway-specific gene expression interact with each other. Steroid hormone receptors inhibit the action of the transcription factor AP-1 (Fos/Jun) and vice versa. This inhibitory interaction is predominantly effected at the level of protein-protein contact without the need for the interfering transcription factor to bind to DNA. In some cases the two pathways function additively or even synergistically resulting in cooperation of the transcription factors in regulation of gene expression. The examples to be discussed in this text document how elaborate and important cross-talks between signal transduction pathways are. This is particularly demonstrated by the fine tuning and reversibility of these processes.

Animals↗

PubMed1992

Effects of chronic nicotine and haloperidol administration on muscarinic receptor-mediated phosphoinositide turnover in rat brain slices.

Muscarinic receptor-mediated phosphoinositide (PI) turnover in rat brain slices was assessed after chronic administration of nicotine (12 mg/kg/day) or haloperidol decanoate (1.5 mg/kg/day), either alone or in combination, for 6 weeks. Nicotine alone did not significantly alter carbachol-induced inositol monophosphate (IP1) accumulation in the frontal cortex, but did result in a significant increase in the hippocampus, and in a decrease in the striatum. Haloperidol alone attenuated carbachol-stimulated IP1 accumulation in all three brain regions. Chronic treatment with combined nicotine and haloperidol resulted in no significant change in carbachol-sensitive IP1 accumulation in either the frontal cortex or hippocampus but did result in a decrease in the striatum. The results suggest significant cross-talk between cholinergic and dopaminergic systems in affecting PI metabolism.

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↗

PubMedDate not supplied

Alpha- and beta-adrenoceptor cross-talk in the regulation of glycogenolysis in dog and guinea-pig liver.

The dog liver glycogenolytic response to isoprenaline (EC50 = 3 x 10(-9) M) was selectively blocked by 10(-5) M of practolol, but not by butoxamine. In contrast, the glycogenolytic response to isoprenaline (EC50 = 3 x 10(-7) M) was inhibited by 10(-6) M of butoxamine, but not by practolol, in the guinea-pig liver. This suggests that, in the dog, the isoprenaline response is dominated by beta 1-adrenoceptors, while in the guinea-pig beta 2-receptors control such response. Glucose release from dog and guinea-pig liver slices was also stimulated by amidephrine (EC50 = 10(-6) M in the dog and 4 x 10(-5) M in the guinea-pig). Both prazosin and yohimbine blocked this response. The effectiveness of clonidine as a glucose-mobilizing agent could only be established in the dog liver. Prazosin showed greater activity than yohimbine in antagonizing the response to both agonists. In the dog, low concentrations of alpha-adrenoceptor agonists (10(-9) M), that failed to modify the basal glucose release per se, selectively depressed the isoprenaline response. Prazosin, but not yohimbine, reversed this inhibitory effect. It is concluded that glucose release from the dog liver is regulated by two opposite mechanisms that seem to be associated to alpha 1-adrenoceptors (inhibitory) and to beta 1-adrenoceptors (stimulatory).

Adrenergic alpha-Agonists↗

PubMed1992

Signal transduction pathways in keratinocytes.

Mammalian cells do not live as isolated organisms, but are instead organized into complex, highly specialized tissue organs composed of a homogeneous or a mixed cell population. In order to maintain tissue homeostasis in physiological and pathophysiological conditions, intercellular communication is an absolute requirement. This review will summarize our current knowledge as to how an extracellular signal is transduced via a specific receptor to the interior of the cell and how this signal will induce special cell functions. Attention will be paid to the major signal transduction pathways known to be active in keratinocytes, namely the adenylate cyclase, guanylate cyclase, tyrosine kinase, and phospholipase C systems. Finally, examples will be given of how interactions between these signal transduction pathways can take place and how 'signal cross-talk' might regulate keratinocyte function.

Adenylyl Cyclases↗

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↗

PubMed1992

Tyrosine phosphorylation of G protein alpha subunits by pp60c-src.

A number of lines of evidence suggest that cross-talk exists between the cellular signal transduction pathways involving tyrosine phosphorylation catalyzed by members of the pp60c-src kinase family and those mediated by guanine nucleotide regulatory proteins (G proteins). In this study, we explore the possibility that direct interactions between pp60c-src and G proteins may occur with functional consequences. Preparations of pp60c-src isolated by immunoprecipitation phosphorylate on tyrosine residues the purified G-protein alpha subunits (G alpha) of several heterotrimeric G proteins. Phosphorylation is highly dependent on G-protein conformation, and G alpha(GDP) uncomplexed by beta gamma subunits appears to be the preferred substrate. In functional studies, phosphorylation of stimulatory G alpha (G alpha s) modestly increases the rate of binding of guanosine 5'-[gamma-[35S]thio]triphosphate to Gs as well as the receptor-stimulated steady-state rate of GTP hydrolysis by Gs. Heterotrimeric G proteins may represent a previously unappreciated class of potential substrates for pp60c-src.

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↗

PubMed1991

Involvement of protein kinase-C in the effect of angiotensin-II on adenosine 3',5'-monophosphate production in lactotroph cells.

When applied to rat anterior pituitary cells, angiotensin-II (AII) exerted two opposite effects on adenylate cyclase (AC) activity: a pertussis toxin (PTX)-sensitive inhibition of the enzyme with a maximal effect of -42 +/- 2% in crude cell membrane preparations, and, in contrast, a non-PTX-sensitive stimulation of cAMP production (maximal effect = 38 +/- 3%) in intact cells. The apparent affinity of both effects was equal to 1.8 nM. The stimulation of cAMP formation parallels the stimulation of PRL release. Under the same conditions, dopamine (DA) inhibited both membrane AC activity and cAMP formation in intact cells by a PTX-sensitive mechanism. After separation of pituitary cell types by sedimentation at unit gravity, the effects of AII and DA on intracellular cAMP and membrane AC activity coincided in the same fractions (those enriched in PRL cells). The stimulatory effect of AII on cAMP formation was about 5 times weaker than that of peptides positively coupled to AC as vasoactive intestinal peptide in total as well as in PRL-enriched cells. Since the AII receptor is also coupled to phospholipase-C (PLC) in a non-PTX-sensitive manner, we investigated whether protein kinase-C (PKC) could indirectly account for the positive effect of AII on cAMP formation. 12-O-Tetradecanolylphorbol 13-acetate (TPA), a stimulator of PKC was indeed able to increase intracellular cAMP; this effect was not additive with that of AII. conversely, application of the PKC inhibitors H7 [1-(5-isoquinolylsulfonyl)2-methyl-piperazine] and staurosporine or desensitization of PKC by long exposure of the cells to TPA abolished the cAMP response to TPA as well as that to AII. In addition, thyreoliberin, another activator of the PLC pathway, was able to stimulate cAMP formation in a PKC-dependent manner. DA inhibition of intracellular cAMP was not affected by any PKC inhibition. We conclude that in lactotroph cells, 1) the AII inhibitory coupling to AC observed in membrane preparations does not exist in intact cells, at least under basal conditions; and 2) the AII intracellular cAMP stimulation observed is not accounted for by a direct coupling with AC; it is due to a cross-talk of the PLC pathway mediated by PKC, an effect that might be shared by other PLC-stimulating mediators and may participate in the regulation of PRL release.

Adenylyl Cyclases↗