Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of several chemically related chloride channel blocking drugs was investigated on the adrenocorticotropic hormone (ACTH) secretory process in mouse clonal AtT-20 corticotrophs. When cells were simultaneously exposed to diphenylamine-2-carboxylate (DPC) or related substances (Hoechst compounds 131, 143, and 144) and the adenylate cyclase activator forskolin, ACTH secretion was inhibited by 76-95% [half-maximal inhibitory concentration (IC50) 450, 15, 84, and 32 microM, respectively]. All four compounds also blocked forskolin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) synthesis in AtT-20 cells by 51-87% (IC50 190, 29, 100, and 130 microM for DPC and compounds 131, 143, and 144, respectively). Pertussis toxin pretreatment of cells caused a partial reversal of DPC-inhibited forskolin-stimulated cAMP formation. The toxin had no effect on inhibition of forskolin-stimulated ACTH secretion by DPC. Secretion of ACTH in response to cAMP-independent stimulants such as the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate or the calcium channel agonist BAY K 8644 were blocked by compound 131 as was the secretory response to 8-bromoadenosine 3',5'-cyclic monophosphate. These results suggest that phenylanthranilic acids have adenylate cyclase inhibiting action but that the postcyclase activity is more relevant to the ability of these compounds to block ACTH secretion. DPC also blocked 125I efflux (an index of Cl- secretion) from AtT-20 cells. Because an increase in osmotic strength of the culture media reduced forskolin-stimulated ACTH secretion, these data suggest that DPC and related compounds may negatively modulate chloride-dependent osmotically driven ACTH secretion from AtT-20 cells.
 ...
PMID:Chloride channel blockers inhibit ACTH secretion from mouse pituitary tumor cells. 170 5

In AtT-20 cells somatostatin inhibits the secretion of adrenocorticotropic hormone (ACTH) through the activation of GTP binding proteins (G proteins) linked to second messengers such as calcium and cyclic AMP (cAMP). Recently, it has been proposed that there may be G proteins that regulate directly the exocytotic machinery. We have investigated whether somatostatin could inhibit secretion at a step distal to second messengers through a GTP binding protein. For these studies two experimental paradigms were used: (1) intact cells stimulated by calcium ionophores and (2) digitonin-permeabilized cells exposed to buffers of increasing Ca2+ concentrations. Somatostatin inhibited by 70% the ACTH release caused by the calcium ionophore ionomycin without modifying the ionophore-induced elevation in cytosolic [Ca2+]. This effect was cAMP independent because (1) it was observed in the presence of high concentrations of membrane-permeant cAMP analogues, and (2) it was not accompanied by a change in cAMP levels. The effect was also independent of the levels of activators of protein kinase C because it could be produced in the presence of high concentrations of phorbol esters. The action of somatostatin was prevented by pertussis toxin. In digitonin-permeabilized AtT-20 cells somatostatin inhibited release induced by calcium buffers in a GTP-dependent manner. These two observations indicate the involvement of a G protein. It is proposed that a G protein coupled to somatostatin receptors inhibits the intracellular machinery of secretion at a step distal to second messengers, perhaps at the exocytotic site.
 ...
PMID:Evidence that receptor-linked G protein inhibits exocytosis by a post-second-messenger mechanism in AtT-20 cells. 196 44

Bordetella pertussis synthesizes a variety of virulence factors including a calmodulin-dependent adenylate cyclase (AC) toxin. Treatment of anterior pituitary cells with this AC toxin resulted in an increase in cellular cAMP levels that was associated with accelerated exocytosis of growth hormone (GH), prolactin, adrenocorticotropic hormone (ACTH), and luteinizing hormone (LH). The kinetics of release of these hormones, however, were markedly different; GH and prolactin were rapidly released, while LH and ACTH secretion was more gradually elevated. Neither dopamine agonists nor somatostatin changed the ability of AC toxin to generate cAMP (up to 2 h). Low concentrations of AC toxin amplified the secretory response to hypophysiotrophic hormones. We conclude that bacterial AC toxin can rapidly elevate cAMP levels in anterior pituitary cells and that it is this response that explains the subsequent acceleration of hormone release.
 ...
PMID:Prokaryotic adenylate cyclase toxin stimulates anterior pituitary cells in culture. 301 20

The mouse adrenocortical Y-1 cell line has been found to express high affinity binding sites for neuropeptide Y (NPY). Pharmacological studies have shown that these NPY binding sites are of the Y1 type. Reverse transcription-polymerase chain reaction using primers specific for the rat Y1 receptor revealed that the NPY Y1 receptor mRNA is present in Y-1 cells. The Kd of the receptor for NPY was found to be 1.75 +/- 0.20 nM and the Bmax was 265 +/- 18 fmol/mg. The NPY Y1 receptors in this adrenocortical cell line were shown to be coupled to pertussis toxin-sensitive G proteins. Stimulation of Y1 receptors resulted in the inhibition of forskolin- and adrenocorticotropic hormone (ACTH)-stimulated cAMP synthesis. NPY had no effect on basal steroid release from the Y-1 cells. At an ACTH concentration of 0.1 microM, NPY did not affect ACTH-stimulated steroid release, although NPY did inhibit cAMP production under the same hormonal conditions. cAMP profoundly affected the density of the NPY receptors in Y-1 cells. Treatment of the cells with N6,2'-O-dibutyryl-cAMP or ACTH reduced the Y1 receptor density by > 50%. On the other hand the steroid dexamethasone increased the density of Y1 receptors by 35%. Although additional detailed studies are necessary, these results may have interesting implications for the functions of ACTH, steroids, and NPY in the pituitary-adrenocortical axis.
 ...
PMID:Studies on neuropeptide Y receptors in a mouse adrenocortical cell line. 762 80

Histamine H3 receptors have been identified in rat and guinea-pig pituitary glands and in the mouse pituitary tumor cell line, AtT-20. Histamine H3 receptor agonists are reported to stimulate adrenocorticotropic hormone (ACTH) release from AtT-20 cells, an effect blocked by histamine H3 but not H1 or H2 receptor antagonists. To determine whether negative feedback regulation of the histamine H3 receptor-mediated effect might occur, we tested the effects of steroid treatment upon binding of the agonist [3H]N alpha-methylhistamine to AtT-20 cell membranes. Consistent with feedback regulation, steroid treatment of the cells reduced [3H]N alpha-methylhistamine binding. The effect was dose-dependent and was greatest for glucocorticoids among the steroids tested. As the duration of steroid treatment increased, the amount of [3H]N alpha-methylhistamine binding decreased, to 15% of control at 36 h. However, the effect was not specific for histamine H3 receptors. Somatostatin inhibits ACTH release from these cells and its binding was similarly reduced by steroid treatment. Because steroids have been reported to modulate levels of guanine nucleotide-binding proteins, the lack of receptor specificity could reflect an indirect effect of steroids upon agonist binding and, in fact, we show that [3H]N alpha-methylhistamine binding to these cells, like somatostatin, is pertussis toxin-sensitive. However, steroid treatment does not alter the apparent levels of pertussis toxin substrate in these cells. Whether steroid treatment affects histamine H3 receptors of these cells directly or through some more subtle effect upon the guanine nucleotide-binding proteins to which they couple, the result is a negative feedback loop that attenuates [3H]N alpha-methylhistamine binding to these cells.
 ...
PMID:Steroid-sensitivity of agonist binding to pituitary cell line histamine H3 receptors. 808 74

The alpha 2A-adrenergic receptor (alpha 2AAR), via its interaction with the pertussis toxin-sensitive Gi/G(o) class of G proteins, modulates multiple effector systems, including inhibition of adenylyl cyclase and Ca2+ channels and activation of K+ channels. Mutation of a membrane-embedded aspartate residue, highly conserved among G protein-coupled receptors, in the alpha 2AAR to asparagine (D79N alpha 2AAR) results in selective uncoupling of the receptor to K+ currents but retention of inhibition of cAMP production and of voltage-sensitive Ca2+ currents when expressed in AtT20 anterior pituitary cells in culture. It is known that attenuation of cAMP synthesis alone cannot account for alpha 2AAR suppression of stimulus-secretion coupling; thus, the D79N alpha 2AAR provides a unique tool with which to assess the relative contribution of K+ current activation and Ca2+ current suppression in mediating the cellular responses of alpha 2AAR. The wild-type alpha 2AAR suppresses basal and secretagogue-evoked adrenocorticotropic hormone (ACTH) release in a manner indistinguishable from response to the endogenous somatostatin receptor. In contrast, the D79N alpha 2AAR does not attenuate basal ACTH release and is only partially effective in suppressing ACTH secretion evoked by the secretagogue isoproterenol. Regulation of ACTH release evoked by 8-bromo-cAMP, which bypasses receptor regulation of cAMP synthesis, suggests that attenuation of cAMP production, although not sufficient for inhibition of ACTH secretion, nevertheless participates in a functionally relevant manner. Taken together, the present findings indicate that alpha 2AAR-mediated suppression of neuropeptide secretion requires concomitant regulation of K+ and Ca2+ currents in parallel with attenuation of cAMP production.
 ...
PMID:Genetic evidence for involvement of multiple effector systems in alpha 2A-adrenergic receptor inhibition of stimulus-secretion coupling. 870 Jan 25

Bovine adrenal zona fasciculata (AZF) cells express a noninactivating K+ current (IAC) that is inhibited by adrenocorticotropic hormone (ACTH) at picomolar concentrations. Inhibition of IAC may be a critical step in depolarization-dependent Ca2+ entry leading to cortisol secretion. In whole-cell patch clamp recordings from AZF cells, we have characterized properties of IAC and the signalling pathway by which ACTH inhibits this current. IAC was identified as a voltage-gated, outwardly rectifying, K(+)-selective current whose inhibition by ACTH required activation of a pertussis toxin-insensitive GTP binding protein. IAC was selectively inhibited by the cAMP analogue 8-(4-chlorophenylthio)-adenosine 3':5'-cyclic monophosphate (8-pcpt-cAMP) with an IC50 of 160 microM. The adenylate cyclase activator forskolin (2.5 microM) also reduced IAC by 92 +/- 4.7%. Inhibition of IAC by ACTH, 8-pcpt-cAMP and forskolin was not prevented by the cAMP-dependent protein kinase inhibitors H-89 (5 microM), cAMP-dependent protein kinase inhibitor peptide (PKI[5-24]) (2 microM), (Rp)-cAMPS (500 microM), or by the nonspecific protein kinase inhibitor staurosporine (100 nM) applied externally or intracellularly through the patch pipette. At the same concentrations, these kinase inhibitors abolished 8-pcpt-cAMP-stimulated A-kinase activity in AZF cell extracts. In intact AZF cells, 8-pcpt-cAMP activated A-kinase with an EC50 of 77 nM, a concentration 2,000-fold lower than that inhibiting IAC half maximally. The active catalytic subunit of A-kinase applied intracellularly through the recording pipette failed to alter functional expression of IAC. The inhibition of IAC by ACTH and 8-pcpt-cAMP was eliminated by substituting the nonhydrolyzable ATP analogue AMP-PNP for ATP in the pipette solution. Penfluridol, an antagonist of T-type Ca2+ channels inhibited 8-pcpt-cAMP-induced cortisol secretion with an IC50 of 0.33 microM, a concentration that effectively blocks Ca2+ channel in these cells. These results demonstrate that IAC is a K(+)-selective current whose gating is controlled by an unusual combination of metabolic factors and membrane voltage. IAC may be the first example of an ionic current that is inhibited by cAMP through an A-kinase-independent mechanism. The A-kinase-independent inhibition of IAC by ACTH and cAMP through a mechanism requiring ATP hydrolysis appears to be a unique form of channel modulation. These findings suggest a model for cortisol secretion wherein cAMP combines with two separate effectors to activate parallel steroidogenic signalling pathways. These include the traditional A-kinase-dependent signalling cascade and a novel pathway wherein cAMP binding to IAC K+ channels leads to membrane depolarization and Ca2+ entry. The simultaneous activation of A-kinase- and Ca(2+)-dependent pathways produces the full steroidogenic response.
 ...
PMID:Adrenocorticotropic hormone and cAMP inhibit noninactivating K+ current in adrenocortical cells by an A-kinase-independent mechanism requiring ATP hydrolysis. 889 75