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

We have examined the functional consequences of G protein coupling to calcium-activated potassium (KCa) channels using isometric tension records from guinea pig tracheal smooth muscle. After incubation with 1 microgram/ml pertussis toxin (PTX) for 6 h, the contraction response to 1 microM methacholine (MCh) was suppressed by 31.7 +/- 5.0% (n = 10). Similarly, the contraction was inhibited by 29.1 +/- 5.0% (n = 6) after application of 0.1 microM AF-DX 116, an M2-selective muscarinic receptor antagonist. Cholera toxin (CTX, 2.0 micrograms/ml for 6 h), which activates the stimulatory G protein of adenylyl cyclase (Gs), also suppressed contraction by 43.9 +/- 3.3% (n = 11). The inhibitory effects of PTX, AF-DX 116, or CTX were reversed in the presence of 100 nM charybdotoxin (ChTX), a selective KCa channel inhibitor. These findings suggest that disruption of inhibitory coupling between muscarinic receptor and KCa channels mediated by PTX-sensitive G proteins, or KCa channel activation induced by Gs/adenylyl cyclase-linked processes, antagonizes muscarinic contraction. The isoproterenol concentration-inhibition curves for precontracted trachea (1 microM MCh) were shifted to the left after perfusion with PTX or AF-DX 116, and the leftward shift of the curve was blocked by ChTX. Thus direct or indirect regulation of KCa channels mediated by the inhibitory guanine nucleotide binding protein (Gi) and Gs may play a functionally important role in the mechanical antagonism by the two receptor agonists.
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PMID:Role of G proteins and KCa channels in the muscarinic and beta-adrenergic regulation of airway smooth muscle. 786 43

Na+ channels in acutely dissociated rat hippocampal neurons and in Chinese hamster ovary (CHO) cells transfected with a cDNA encoding the alpha subunit of rat brain type IIA Na+ channel (CNaIIA-1 cells) are modulated by guanine nucleotide binding protein (G protein)-coupled pathways under conditions of whole-cell voltage clamp. Activation of G proteins by 0.2-0.5 mM guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]), a nonhydrolyzable GTP analog, increased Na+ currents recorded in both cell types. The increase in current amplitude was caused by an 8- to 10-mV negative shift in the voltage dependence of both activation and inactivation. The effects of G-protein activators were blocked by treatment with pertussis toxin or guanosine 5'-[beta-thio]diphosphate (GDP[beta S]), a nonhydrolyzable GDP analog, but not by cholera toxin. GDP[beta S] (2 mM) alone had effects opposite those of GTP[gamma S], shifting Na(+)-channel gating 8-10 mV toward more-positive membrane potentials and suggesting that basal activation of G proteins in the absence of stimulation is sufficient to modulate Na+ channels. In CNaIIA-1 cells, thrombin, which activates pertussis toxin-sensitive G proteins in CHO cells, caused a further negative shift in the voltage dependence of Na(+)-channel activation and inactivation beyond that observed with GTP alone. The results in CNaIIA-1 cells indicate that the alpha subunit of the Na+ channel alone is sufficient to mediate G protein effects on gating. The modulation of Na+ channels via a G-protein-coupled pathway acting on Na(+)-channel alpha subunits may regulate electrical excitability through integration of different G-protein-coupled synaptic inputs.
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PMID:Modulation of brain Na+ channels by a G-protein-coupled pathway. 799 31

In gallbladder smooth muscle, carbachol interacts with M3 receptors to mediate contraction. To examine components of the intracellular second messenger system that is coupled to these receptors we have tested whether carbachol stimulates the formation of inositol phosphates (IP) to cause contraction. Guinea pig gallbladder muscle strips were prelabeled with [3H]inositol and were incubated with 0.1 mmol/l carbachol, a concentration causing maximal contraction. [3H]inositol monophosphates, [3H]inositol bisphosphates and [3H]inositol trisphosphates and contraction were measured at various times (0-90 s). To examine whether a pertussis toxin-sensitive guanine nucleotide binding protein is coupled to the muscarinic receptors, guinea pigs were pretreated with pertussis toxin (180 micrograms/kg i.v./24 h). The effectiveness of pertussis toxin treatment was determined by measuring [32P]ADP-ribosylation of a approximately 40/41 kDa protein from gallbladder homogenates. Carbachol caused a significant time-dependent increase in the formation of [3H]inositol monophosphates, [3H]inositol bisphosphates and [3H]inositol trisphosphates. The time course of [3H]inositol trisphosphate turnover caused by carbachol was biphasic, and was detectable at 15 s and maximal at 60 s; at 75 s and 90 s formation of [3H]inositol trisphosphates decreased, whereas the time course of carbachol-induced contraction of the gallbladder smooth muscle strips reached a plateau after 90 s. The effects of carbachol on [3H]inositol trisphosphates and on contraction were abolished by atropine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Signal transduction pathway of the muscarinic receptors mediating gallbladder contraction. 805 6

The cytokine-mediated stimulation of sphingomyelin (SM) metabolism is emerging as an important signal transduction pathway via the generation of ceramide and sphingosine, products which have been shown to affect a wide variety of biological processes. Because SM-mediated signal transduction is initiated via the hydrolysis of an integral membrane phospholipid by a phospholipase C-like enzyme (sphingomyelinase) to yield lipids which modulate protein kinase C activity, the SM and phosphatidylinositol (PI) signaling pathways share certain similarities. The present study was undertaken to examine the potential for interplay between SM and PI turnover by testing the effects of sphingosine, sphingosine-1-phosphate, and ceramide on PI turnover. In dermal fibroblasts, sphingosine stimulated a rapid dose-dependent hydrolysis of PI, yielding inositol 1,4,5-triphosphate, followed by increased levels of intracellular calcium. Sphingosine-induced inositol phosphate (IP) accumulation was observed between 5 and 30 microM sphingosine with a maximal accumulation of 2.7-fold over control levels. Enhanced IP formation was measured as early as 5 s following sphingosine treatment and IP levels remained elevated for more than 60 min. Intracellular calcium mobilization accompanied the dose-dependent accumulation of IPs in response to sphingosine, although this effect was not apparent until after a 30-40-s lag period. Interestingly, sphingosine-1-phosphate stimulated a more rapid release of intracellular Ca2+ than sphingosine, but it had no effect on PI turnover. DL-threo-Dihydrosphingosine, a competitive inhibitor of sphingosine kinase, stimulates both PI turnover and Ca2+ flux, but does not block the action of sphingosine relative to those two processes. Ceramide (added as C2-ceramide), N-stearylamine, and stearoyl-D-sphingosine did not affect PI turnover or Ca2+ mobilization. Pretreatment of intact cells with pertussis toxin partially inhibited sphingosine-mediated IP accumulation, suggesting a role for guanine nucleotide binding protein(s) (G protein) in sphingosine-stimulated PI turnover. Furthermore, guanosine 5'-O-(3-thiotriphosphate) stimulated, whereas guanosine 5'-O-(2-thiodiphosphate) inhibited, sphingosine-induced IP accumulation in permeabilized cells. Collectively, these data suggest that sphingosine enhances PI turnover by stimulating phospholipase C activity, and the activation of this process may be modulated by G protein interactions. Thus, the regulation of PI turnover and Ca2+ mobilization by sphingosine may represent another mechanism by which sphingosine modulates cell function and that these effects can be distinguished from those of ceramide.
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PMID:Sphingosine-mediated phosphatidylinositol metabolism and calcium mobilization. 811 27

Adenosine and acetylcholine exert negative chronotropic and anti-adrenergic effects on nonischemic myocardium presumably via receptor coupling to the same or similar inhibitory guanine nucleotide binding protein (Gi). To determine whether the cardioprotective effect of adenosine is mediated via adenosine A1 receptor coupling to Gi proteins, isolated rat hearts, perfused at constant pressure and constant heart rate, were subjected to 30 min global normothermic (37 degrees C) ischemia and 45 min reperfusion. Untreated control hearts recovered 52 +/- 2% of preischemic left ventricular developed pressure (LVDP). Hearts treated for 10 minutes prior to ischemia with adenosine (100 microM) and the adenosine A1 receptor agonist cyclohexyladenosine (CHA, 0.25 microM) recovered 67 +/- 4% and 70 +/- 4%, respectively. Hearts treated with the non-specific muscarinic cholinergic agonist carbamylcholine (1 microM) exhibited similar enhanced postischemic recovery (70 +/- 3%). Pretreatment of rats with pertussis toxin (25 micrograms/kg i.p., 48 h prior to isolation) significantly reduced the negative chronotropic effects of adenosine and CHA. Pertussis toxin pretreatment also blocked the beneficial effects of adenosine (57 +/- 4% recovery) and CHA (49 +/- 4% recovery) on postischemic function. These results support the hypothesis that the salutary effect of adenosine on the ischemic myocardium is mediated via adenosine A1 receptor coupling to a pertussis toxin sensitive G protein, presumably Gi.
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PMID:Pertussis toxin blocks adenosine A1 receptor mediated protection of the ischemic rat heart. 823 Feb 43

Studies were performed to identify the site at which activation of protein kinase C (PKC) inhibits arginine vasopressin (AVP)-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in cultured rat inner medullary collecting tubule (RIMCT) cells. Neither endogenous stimulation of PKC by epidermal growth factor (EGF) nor the addition of exogenous 1,2-dioctanoyl-sn-glycerol (DOG) impaired forskolin-stimulated cAMP accumulation. Similarly, neither EGF nor DOG altered cAMP generation in response to cholera toxin. However, pretreatment of RIMCT cells with pertussis toxin resulted in loss of inhibition of AVP-stimulated cAMP accumulation by DOG. Likewise, the ability of the phorbol ester, phorbol 12-myristate 13-acetate (PMA), to inhibit AVP-stimulated cAMP accumulation was eliminated by pretreatment with pertussis toxin. PMA also inhibited AVP-stimulated adenylyl cyclase activity in plasma membranes prepared from rat inner medullas. In contrast to its effects on AVP, activation of PKC did not impair cAMP accumulation in response to isoproterenol or prostaglandin E2. These studies demonstrate that PKC-mediated inhibition of AVP-stimulated cAMP accumulation in cultured RIMCT cells requires the intact inhibitory guanine nucleotide binding protein Gi.
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PMID:Protein kinase C inhibits arginine vasopressin-stimulated cAMP accumulation via a Gi-dependent mechanism. 838 49

1. We have previously demonstrated that M2 and M3 muscarinic receptors coexist in the circular smooth muscle of canine proximal colon. Activation of receptors of the M2 subtype leads to inhibition of adenylyl cyclase activity through the GTP-binding protein, Gi, while M3 receptors are coupled to a pertussis toxin-insensitive GTP-binding protein and mediate phosphoinositide hydrolysis. 2. In the present study, the interactions between these second messenger systems were examined. Activation of either protein kinase C or adenosine 3':5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase attenuated carbachol-stimulated phosphoinositide hydrolysis without affecting basal activity. Activation of both protein kinases produced greater attenuation of inositol 1,4,5-trisphosphate formation than activation of either kinase alone. 3. In contrast to its inhibitory effect on phosphoinositide hydrolysis, activation of protein kinase C had no effect on adenylyl cyclase activity. 4. Activation of protein kinase C by phorbol ester treatment resulted in the sequestration of M3 muscarinic receptors from the cell surface without effecting the M2 muscarinic receptor population. Sequestered M3 muscarinic receptors were not rapidly degraded. 5. In contrast, elevation of cellular cyclic AMP decreased the affinity of cell surface muscarinic receptors for an antagonist radioligand without affecting their density. 6. Muscarinic agonist binding was not affected by either activation of protein kinase C or elevation of cellular cyclic AMP. 7. These data support the notion of negative feedback by protein kinase C and cyclic AMP-dependent protein kinase on phosphoinositide hydrolysis. In canine colonic circular smooth muscle this negative feedback regulation of inositol phosphate generation by muscarinic receptor stimulation does not appear to involve the guanine nucleotide binding protein:receptor interaction.
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PMID:Protein kinase regulation of muscarinic receptor signalling in colonic smooth muscle. 838 29

PTH-related protein (PTHrP), the major mediator of hypercalcemia of malignancy, reduces tubular phosphate (Pi) reabsorption through its PTH-like renotropic actions. Another peptide detected in tumoral cells, transforming growth factor-beta (TGF beta), has been shown to considerably suppress the sodium-dependent Pi transport system present in the apical membrane of renal epithelial cells. The unexplored interactions between TGF beta and PTHrP were examined in opossum kidney (OK) cells. Using confluent OK cells, we showed that TGF beta attenuated the inhibition of Pi transport mediated by PTHrP. Similarly, 18 h TGF beta incubation resulted in a substantial reduction of the cAMP response elicited by PTHrP without apparent involvement of pertussis toxin-sensitive guanine nucleotide binding protein(s). The number of PTHrP(1-34) binding sites in TGF beta-treated cells was decreased with the affinity unchanged. Forskolin- and prostaglandin E2-stimulated cAMP productions were not significantly altered by TGF beta treatment. Therefore, TGF beta reduced Pi transport in OK cells, modulated the actions of PTHrP, and decreased its receptor number. Whether this happens in vivo is as yet unknown.
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PMID:Transforming growth factor-beta modulates the parathyroid hormone-related protein-induced responses in renal epithelial cells. 839 20

1. Ca(2+)-channel modulation by adenosine was investigated in enzymatically dispersed adult rat superior cervical ganglion (SCG) neurons using the whole-cell variant of the patch-clamp technique. 2. Adenosine produced a concentration-dependent decrease in the Ca(2+)-current amplitude with an EC50 of 174 nM and maximum inhibition of 36%. The effects of adenosine on the Ca2+ current were both time and voltage dependent. The inhibition was maximal at +10 mV and decreased at either hyperpolarizing or depolarizing potentials. 3. The inhibitory response desensitized after prolonged (> 1 min) exposure to 10 microM adenosine, whereas multiple brief (< 30 s) applications slightly decreased the subsequent response. 4. Adenosine-induced Ca2+ current inhibition was mediated by an A1-type adenosine receptor, because the half-maximal inhibition value for an A1 receptor selective agonist, chloro-N-cyclopentyladenosine, was 1,000-fold lower than that for an A2 receptor selective agonist, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarbozamido adenosine hydrochloride (33 nM vs. 40 microM, respectively). 5. A guanine nucleotide binding protein (G protein) appeared to be involved in the action of adenosine, because: 1) the adenosine-induced current inhibition could be largely relieved by depolarizing voltage prepulses; 2) tail current analysis revealed that adenosine shifted Ca(2+)-channel activation to more depolarized potentials; and 3) adenosine inhibition was abolished by 2 mM intracellular guanosine 5'-O-(2-thiodiphosphate) or 500 ng/ml pertussis toxin pretreatment. 6. Adenosine did not appear to inhibit L-type Ca2+ channels, because the prolonged tail current component induced by the dihydropyridine "agonist" 2,6-dimethy-3-carbomethoxy-5-nitro-4-(2-trifluoromethyl-phenyl)- 1,4-dihydropyridine (2 microM) was not affected by adenosine. 7. Adenosine-induced inhibition was reduced to approximately 15% after application of 10 microM omega-conotoxin GVIA, suggesting that adenosine primarily inhibits N-type Ca2+ channels. The Ca(2+)-current component resistant to omega-conotoxin GVIA was also resistant to omega-agatoxin IVA (200 nM), suggesting a lack of P-type of Ca2+ channels in SCG neurons. 8. In conclusion, adenosine produces a dose-, time-, and voltage-dependent inhibition of Ca2+ currents in SCG neurons. Adenosine acts on an A1 adenosine receptor subtype in SCG neurons via a pertussis toxin-sensitive G protein to inhibit N-type Ca2+ channels and an unidentified Ca(2+)-current component. Modulation of Ca2+ currents by adenosine may be an important mechanism for its inhibitory effect on neurotransmitter release in sympathetic neurons.
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PMID:Adenosine modulates voltage-gated Ca2+ channels in adult rat sympathetic neurons. 841 Jan 61

Stimulatory guanine nucleotide binding protein (Gs)-coupled receptors activated by luteinizing hormone, vasopressin, and the catecholamine isoproterenol (luteinizing hormone receptor, type 2 vasopressin receptor, and types 1 and 2 beta-adrenergic receptors) and the Gi-coupled M2 muscarinic receptor (M2R) were expressed transiently in COS cells, alone and in combination with Gbeta gamma dimers, their corresponding Galphas (Galpha(s), or Galpha(i3)) and either Galpha(q) or Galpha(16). Phospholipase C (PLC) activity, assessed by inositol phosphate production from preincorporated myo[3H]inositol, was then determined to gain insight into differential coupling preferences among receptors and G proteins. The following were observed: (i) All receptors tested were able to stimulate PLC activity in response to agonist occupation. The effect of the M2R was pertussis toxin sensitive. (ii) While, as expected, expression of Galpha(q) facilitated an agonist-induced activation of PLC that varied widely from receptor to receptor (400% with type 2 vasopressin receptor and only 30% with M2R), expression of Galpha(16) facilitated about equally well the activation of PLC by any of the tested receptors and thus showed little if any discrimination for one receptor over another. (iii) Gbeta gamma elevated basal (agonist independent) PLC activity between 2- and 4-fold, confirming the proven ability of Gbeta gamma to stimulate PLCbeta. (iv) Activation of expressed receptors by their respective ligands in cells coexpressing excess Gbeta gamma elicited agonist stimulated PLC activities, which, in the case of the M2R, was not blocked by pertussis toxin (PTX), suggesting mediation by a PTX-insensitive PLC-stimulating Galpha subunit, presumably, but not necessarily, of the Gq family. (v) The effects of Gbeta gamma and the PTX-insensitive Galpha elicited by M2R were synergistic, suggesting the possibility that one or more forms of PLC are under conditional or dual regulation of G protein subunits such that stimulation by one sensitizes to the stimulation by the other.
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PMID:G protein subunits and the stimulation of phospholipase C by Gs-and Gi-coupled receptors: Lack of receptor selectivity of Galpha(16) and evidence for a synergic interaction between Gbeta gamma and the alpha subunit of a receptor activated G protein. 861 Jan 26


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