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 chronotropic response of the heart to alpha 1-adrenergic catecholamines influenced by pertussis toxin under certain conditions. In view of the fact that alpha 1-adrenergic action is mediated by the phosphatidylinositol pathway of hormone action in many cells, we examined the hypothesis that alpha-adrenergic agonists stimulate phosphatidylinositol hydrolysis in cardiomyocytes and that this effect is sensitive to pertussis toxin. Addition of norepinephrine to cultured rat ventricular myocytes prelabeled with myo-[2-3H]inositol resulted in rapid and significant accumulation of inositol phosphate (IP1) and inositol biphosphate. Norepinephrine-stimulated IP1 formation was not inhibited by propranolol, but was inhibited by alpha-adrenergic antagonists with an order of potency indicating alpha 1-adrenergic receptor subselectivity: prazosin (alpha 1; 3 nM) greater than yohimbine (alpha 2; 10 microM). The effect of norepinephrine to enhance IP1 formation was markedly attenuated in cells pretreated with pertussis toxin. Pertussis toxin also induced the transfer of ADP-ribose from NAD to a 41,000-dalton membrane protein in these cells. The concentration of pertussis toxin resulting in maximal inhibition of norepinephrine-stimulated IP1 formation correlated well with the concentration of pertussis toxin necessary to completely ADP-ribosylate a 41,000-dalton membrane protein (1 ng/ml). The range over which pertussis toxin inhibited norepinephrine-dependent IP1 formation and ADP-ribosylated the 41,000-dalton substrate was virtually identical. These observations establish a role for a 41,000-dalton pertussis toxin substrate in coupling the alpha 1-adrenergic receptor to phosphoinositol hydrolysis in myocardial cells.
 ...
PMID:A pertussis toxin substrate regulates alpha 1-adrenergic dependent phosphatidylinositol hydrolysis in cultured rat myocytes. 288 98

The production of inositol phosphates in response to carbachol was studied in rat anterior pituitary tissue prelabelled with [3H]inositol. Carbachol (10 microM) stimulated inositol mono-, bis- and trisphosphate production (IP1, IP2 and IP3) by 360 +/- 49, 338 +/- 49 and 503 +/- 49 (mean +/- SEM, P less than 0.001) percent respectively during a 30 min incubation. Mean basal production was 5.4 +/- 0.3, 4.1 +/- 0.5 and 0.9 +/- 0.3 expressed as a percent of total [3H]inositol lipid for IP, IP2 and IP3 respectively. Stimulated inositol phosphate production was dose dependent and detectable after 5 min. Atropine prevented this stimulation indicating mediation via muscarinic receptors. Removal of extracellular Ca2+ reduced both basal and stimulated total inositol phosphate production by 60% and 56% respectively but did not impair carbachol-induced phosphoinositide hydrolysis per se. Pretreatment of pituitary tissue with either somatostatin (5 micrograms/ml) or pertussis toxin (1 microgram/ml) had no effect on either basal or stimulated inositol phosphate production. These results demonstrate a cholinergic stimulation of phosphatidylinositol bisphosphate (PIP2) hydrolysis in the anterior pituitary which may be important in the action of cholinergic agonists on pituitary hormone secretion.
 ...
PMID:Cholinergic stimulation of phosphoinositide hydrolysis in rat anterior pituitary. 289 24

Binding of chemoattractants to specific cell surface receptors on human polymorphonuclear leukocytes (PMNs) initiates a variety of biologic responses, including directed migration (chemotaxis), release of superoxide anions, and lysosomal enzyme secretion. Chemoattractant receptors belong to a large class of receptors which utilize the hydrolysis of polyphosphoinositides to initiate Ca2+ mobilization and cellular activation. Receptor occupancy leads to phospholipase C-mediated hydrolysis of polyphosphoinositol 4,5-bisphosphate (PIP2) yielding inositol 1,4,5-trisphosphate (IP3) and 1,2 sn-diacylglycerol (DAG). These products synergize to initiate cell activation via calcium mobilization (IP3) and protein kinase C activation (DAG). Pertussis toxin, which ADP-ribosylates and inactivates some GTP binding proteins (G proteins), abolishes all chemoattractant-induced responses, including Ca2+ mobilization, IP3 and DAG production, enzyme secretion, superoxide production and chemotaxis. Direct evidence for chemoattractant receptor: G protein coupling was obtained using PMN membrane preparations which contain a Ca2+-sensitive phospholipase C. Hydrolysis of polyphosphoinositides at resting intracellular Ca2+ levels (100 nm) was only observed when the membranes were stimulated with the chemoattractant N-formyl-methyl-leucyl-phenylalanine (fMet-Leu-Phe) in the presence of GTP. Myeloid cells contain two distinct pertussis toxin substrates of similar molecular weight (40 and 41 kD). The 41 kD substrate resembles Gi, whereas a 40 kD substrate is physically associated with a partially purified fMet-Leu-Phe receptor preparation and may therefore represent a novel G protein involved in chemoattractant-stimulated responses. Metabolism of 1,4,5-IP3 to inositol proceeds via two distinct pathways in PMNs: (1) degradation to 1,4-IP2 and 4-IP1 or (2) conversion to 1,3,4,5-IP4, 1,3,4-IP3, 3,4-IP2 and 3-IP1. Initial formation (0-30 s) of 1,4,5-IP3 and DAG occurs at ambient intracellular Ca2+ levels, whereas formation of 1,3,4-IP3 and a second sustained phase of DAG production (30 s-10 min) require elevated cytosolic Ca2+ influx. The later peak of DAG, which is not derived from phosphoinositides, appears to be required for stimulation of respiratory burst activity. Products formed during activation can feed back to attenuate chemoattractant receptor-mediated stimulation of phospholipase C by uncoupling receptor-G protein-phospholipase C interaction.
 ...
PMID:Signal transduction in cells following binding of chemoattractants to membrane receptors. 290 Nov 61

Vasopressin-induced phosphatidylinositol turnover and mobilization of intracellular Ca2+ was studied using an established smooth muscle cell line (A-10). The cells were subcloned to ensure a monoclonal cell population. The accumulation of inositol mono-, di-, and tris-phosphates (IP1, IP2, and IP3, respectively), and the mobilization of intracellular Ca2+ were dependent on the time of incubation and the concentration of arginine vasopressin (AVP). IP1, IP2, and IP3 were significantly elevated after 15 sec and remained elevated for up to 2 hr. The concentrations of AVP required for half-maximal stimulation of IP1, IP2, and IP3 formation were 2, 12, and 4 nM, respectively. LiCl was required to observe the accumulation of inositol phosphates in response to AVP. Significant 45Ca2+ efflux was observed within 15 sec after exposure to AVP. By employing the vasopressin receptor subtype selective antagonists [d(CH2)5Tyr(Me)AVP, V1; d(CH2)5D-Tyr(Et)VAVP,V1/V2; d(CH2) 5D-IleVAVP,V2] and agonists [AVP, V1/V2; dDAVP, V2; dVDAVP, V2], we found that the vasopressin-induced stimulation of phosphatidylinositol turnover and 45Ca2+ efflux were mediated by receptors of the vascular V1 subtype. Pertussis toxin pretreatment partially inhibited vasopressin-induced phosphatidylinositol turnover. These data demonstrate that activation of V1 receptors of vascular smooth muscle cells resulted in enhanced phosphatidylinositol turnover and mobilization of intracellular Ca2+.
 ...
PMID:Vascular vasopressin receptors mediate phosphatidylinositol turnover and calcium efflux in an established smooth muscle cell line. 301 49

Binding of chemoattractants to specific cell surface receptors on polymorphonuclear leukocytes (PMNs) initiates a series of biochemical responses leading to cellular activation. A critical early biochemical event in chemoattractant (CTX) receptor-mediated signal transduction is the phosphodiesteric cleavage of plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2), with concomitant production of the calcium mobilizing inositol-1,4,5-trisphosphate (IP3) isomer, and the protein kinase C activator, 1,2-diacylglycerol (DAG). The following lines of experimental evidence collectively suggest that CTX receptors are coupled to phospholipase C via a guanine nucleotide binding (G) protein. Receptor-mediated hydrolysis of PIP2 in PMN plasma membrane preparations requires both fMet-Leu-Phe and GTP, and incubation of intact PMNs with pertussis toxin (which ADP ribosylates and inactivates some G proteins) eliminates the ability of fMet-Leu-Phe plus GTP to promote PIP2 breakdown in isolated plasma membranes. Studies with both PMN particulate fractions and with partially purified fMet-Leu-Phe receptor preparations indicate that guanine nucleotides regulate CTX receptor affinity. Finally, fMet-Leu-Phe stimulates high-affinity binding of GTP gamma S to PMN membranes as well as GTPase activity. A G alpha subunit has been identified in phagocyte membranes which is different from other G alpha subunits on the basis of molecular weight and differential sensitivity to ribosylation by bacterial toxins. Thus, a novel G protein may be involved in coupling CTX receptors to phospholipase C. Studies in intact and sonicated PMNs demonstrate that metabolism of 1,4,5-IP3 proceeds via two distinct pathways: 1) sequential dephosphorylation to 1,4-IP2, 4-IP1 and inositol, or 2) ATP-dependent conversion to inositol 1,3,4,5-tetrakisphosphate (IP4) followed by sequential dephosphorylation to 1,3,4-IP3, 3,4-IP2, 3-IP1 and inositol. Receptor-mediated hydrolysis of PIP2 occurs at ambient intracellular Ca2+ levels; but metabolism of 1,4,5-IP3 via the IP4 pathway requires elevated cytosolic Ca2+ levels associated with cellular activation. Thus, the two pathways for 1,4,5-IP3 metabolism may serve different metabolic functions. Additionally, inositol phosphate production appears to be controlled by protein kinase C, as phorbol myristate acetate (PMA) abrogates PIP2 hydrolysis by interfering with the ability of the activated G protein to stimulate phospholipase C. This implies a physiologic mechanism for terminating biologic responses via protein kinase C mediated feedback inhibition of PIP2 hydrolysis.
 ...
PMID:Regulation of inositol phospholipid and inositol phosphate metabolism in chemoattractant-activated human polymorphonuclear leukocytes. 312 97

Effects of pertussis toxin or cholera toxin on carbachol-stimulated inositol-1-phosphate ([3H]IP1) accumulation were studied using the human neuroblastoma cell line (SH-SY5Y). The maximal carbachol-stimulated [3H]IP1 accumulation in the SH-SY5Y cells was decreased from 51.4 fmol/10(6) cells to 42.4 fmol/10(6) cells (P less than 0.05) and 22.1 fmol/10(6) cells (P less than 0.01) in the absence and presence of 1 microgram/ml and 10 micrograms/ml pertussis toxin, respectively while the EC50 values did not change. Cholera toxin (1 mg/ml) did not alter carbachol-stimulated [3H]IP1 accumulation in these cells. These results suggest that a pertussis toxin sensitive G-protein may be involved in muscarinic receptor-phosphatidylinositol hydrolysis coupling in SH-SY5Y cells.
 ...
PMID:Muscarinic receptor-mediated hydrolysis of phosphatidylinositols in human neuroblastoma (SH-SY5Y) cells is sensitive to pertussis toxin. 339 Jul 5

The mechanism of morphologic change of human cultured umbilical vein endothelial cells (HUVECs) caused by fibrin was investigated. Ancrod, a thrombin-like enzyme, did not cause morphologic alteration of HUVEC by itself at concentrations ranging from 0.01 to 10 U/ml. However, when 0.02 U/ml of ancrod was added to cultured HUVEC monolayers in the presence of citrated plasma, it caused pronounced morphologic change of HUVEC after 6-10 h incubation period. Gly-Pro-Arg-Pro (4 mg/ml), an inhibitor of fibrin polymerization, prevented the morphologic alteration, indicating that the morphologic alteration was caused by the polymerized fibrin. The morphologic change of HUVEC caused by ancrod-generated fibrin was not observed in the presence of an intracellular calcium mobilization inhibitor TMB-8 (50 microM), and the morphologic alteration was also less pronounced with BAPTA(15 microM)-loaded HUVECs and HUVECs pretreated with EGTA (1.2 mM). Ancrod (in Medium 199) itself did not stimulate phosphoinositide breakdown of HUVEC. However, when ancrod was present in plasma, it caused an increase of [3H]IP1 of HUVECs preloaded with [3H]myoinositol. This IP1 increment was inhibited by Gly-Pro-Arg-Pro. The increase of IP1 was significantly inhibited by the pretreatment of monoclonal antibodies 23C6 and 7E3 directed against alpha v beta 3 integrin. Neomycin (1 mM) and pertussis toxin (100 ng/ml), but not aspirin or mepacrine, blocked this enhanced phosphoinositide breakdown. The morphologic change was also prevented by the monoclonal antibodies, 23C6 and 7E3. These results suggest that both intra- and extra-cellular calcium participate in the event of morphologic change of HUVEC caused by ancrod-generated fibrin, and the morphologic change is mediated, at least in part, by fibrin binding to integrin alpha v beta 3 on HUVECs, causing the subsequent activation of the endogenous G-protein coupled phospholipase C.
 ...
PMID:The morphologic change of endothelial cells by ancrod-generated fibrin is triggered by alpha v beta 3 integrin binding and the subsequent activation of a G-protein coupled phospholipase C. 748 43

1. In rabbit papillary muscles, pretreatment with pertussis toxin (PTX) significantly increased the positive inotropic response to isoprenaline and abolished the inhibitory action of carbachol on the isoprenaline response. 2. Phenylephrine in the presence of propranolol produced a positive inotropic effect and prolonged action potential duration through activation of alpha 1-adrenoceptors. Both of the effects of phenylephrine were significantly enhanced by PTX pretreatment. 3. Accumulation of [3H]inositol monophosphate (IP1) in papillary muscles prelabeled with myo-[3H]inositol was increased by phenylephrine in a concentration-dependent manner, which was antagonized by prazosin. Although PTX pretreatment significantly elevated the basal level of [3H]IP1 formation, the phenylephrine-induced increase in [3H]IP1 formation was unaffected. 4. It is concluded that the cardiac responses to alpha 1-adrenoceptor stimulation studied in these experiments are not transduced by a PTX sensitive G protein (Gi). However, the positive inotropic effect and prolongation of action potential duration mediated by alpha 1-adrenoceptor may be negatively regulated by Gi.
 ...
PMID:Enhancement of the positive inotropic effect mediated by alpha 1-adrenoceptors in pertussis toxin-treated rabbit papillary muscles. 795 41

The kinetic properties of endothelin-1 (ET-1) binding sites and the production of inositol phosphates (IPs; IP1, IP2, IP3), cyclic AMP, thromboxane B2, and prostaglandin F2 alpha induced by various endothelins (ET-1, ET-2, ET-3, and sarafotoxin S6b) were examined in endothelial cells derived from human brain microvessels (HBECs). The presence of both high- and low-affinity binding sites for ET-1 with KD1 = 122 pM and KD2 = 31 nM, and Bmax1 = 124 fmol/mg of protein and Bmax2 = 909 fmol/mg of protein, respectively, was demonstrated on intact HBECs. ET-1 dose-dependently stimulated IP accumulation with EC50 (IP3) = 0.79 nM, whereas ET-3 was ineffective. The order of potency for displacing ET-1 from high-affinity binding sites (ET-1 > ET-2 > sarafotoxin S6b > ET-3) correlated exponentially with the ability of respective ligands to induce IP3 formation. ET-1-induced IP3 formation by HBEC was inhibited by the ETA receptor antagonist, BQ123. The protein kinase C activator phorbol myristate ester dose-dependently inhibited the ET-1-stimulated production of IPs, whereas pertussis toxin was ineffective. Cyclic AMP production by HBECs was enhanced by both phorbol myristate ester and ET-1, and potentiated by combined treatment with ET-1 and phorbol myristate ester. Data indicate that protein kinase C plays a role in regulating the ET-1-induced activation of phospholipase C, whereas interaction of different messenger systems may regulate ET-1-induced accumulation of cyclic AMP. ET-1 also stimulated endothelial prostaglandin F2 alpha production, suggesting that activation of phospholipase A2 is most likely secondary to IP3-mediated intracellular calcium mobilization because both ET-1-induced IP3 and prostaglandin F2 alpha were inhibited by BQ123. These findings are the first demonstration of ET-1 (ETA-type) receptors linked to phospholipase C and phospholipase A2 activation in HBECs.
 ...
PMID:Endothelin-1 receptor binding and cellular signal transduction in cultured human brain endothelial cells. 829 22

The signalling mechanisms whereby high-density lipoproteins (HDL) and low-density lipoproteins (LDL) affect a number of cellular functions in fibroblasts are unclear. This study has analyzed the influence of HDL3 and LDL on the phosphatidylinositol specific phospholipase C pathway in human skin fibroblasts. Exposure of myo-[2-3H]-inositol prelabelled fibroblasts to HDL3 or LDL elicited major increases in IP1 and minor increases in IP2 and IP3 within 30 s. In fura-2 loaded suspended fibroblasts, HDL3 and LDL increased intracellular Ca2+ concentrations ([Ca2+]i) with comparable rapid, transient kinetics. The dose-profiles for HDL3- and LDL-induced increases in [Ca2+]i were also comparable, with half-maximally and maximally effective concentrations being approximately 15 micrograms/mL and approximately 50 micrograms/mL, respectively. HDL3- and LDL-induced increases in [Ca2+]i were diminished by approximately 60% (vs. control fibroblasts) in thapsigargin-pretreated fibroblasts, indicating that release of Ca2+ from intracellular pools is the major contributor toward lipoprotein-induced increases in [Ca2+]i. Pertussis toxin-pretreatment of cells completely abolished lipoprotein induced Ca(2+)-transient, indicating the involvement of a guanine nucleotide-binding protein in the signalling process. In [3H]-palmitic acid-prelabelled fibroblasts, both HDL3 and LDL were observed to stimulate production of DAG. Activation of protein kinase C (PKC) was analysed by determining the cytosol-to-membrane translocation of both enzymatic activity and immunoreactivity of specific PKC isoforms (alpha, delta, epsilon, and zeta). Stimulation with HDL3 and LDL evoked a rapid (within 2.5 min) translocation of PKC activity, with PKC alpha and PKC epsilon being the isoforms translocated. It is concluded that HDL3 and LDL acutely stimulate a phosphoinositide-specific phospholipase C pathway in human skin fibroblasts. However, the specific cell membrane events mediating this signal transduction remain to be further elucidated.
 ...
PMID:High-density lipoprotein and low-density lipoprotein-mediated signal transduction in cultured human skin fibroblasts. 851 99


<< Previous 1 2 3 Next >>