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At least 973 records · Page 54Linked to original sources
PubMed1989

Translocation and activation of protein kinase C in striatal neurons in primary culture: relationship to phorbol dibutyrate actions on the inositol phosphate generating system and neurotransmitter release.

The actions of the tumor-promoting phorbol ester phorbol dibutyrate were examined, under identical physiological conditions, on three distinct cellular processes in striatal neurons: the distribution of protein kinase C, the carbachol-stimulated generation of [3H]inositol monophosphate, and the KCl-evoked release of gamma-[3H]aminobutyric acid ([3H]GABA). Phorbol dibutyrate induced a rapid (complete in 5 min), dose-dependent, entirely reversible (t0.5 = 15 min) translocation of protein kinase C from cytosol to membrane. On longer exposure to phorbol dibutyrate, membrane-associated protein kinase C returned toward the control level, and total cellular enzyme activity declined markedly. Phorbol dibutyrate also induced the dose-dependent attenuation of carbachol-stimulated [3H]inositol monophosphate production and potentiation of KCl-evoked release of [3H]GABA. The translocation of protein kinase C and the potentiation of KCl-evoked [3H]GABA release were both rapidly reversed following washout of phorbol dibutyrate. In addition, for both processes, the effect of a 1-h exposure to phorbol dibutyrate was markedly less than that observed following a 5-min exposure to the agent. In direct contrast, inhibition of carbachol-stimulated [3H]inositol monophosphate production was not rapidly reversed following washout of phorbol dibutyrate and was actually more pronounced following a 1-h exposure, compared with a 5-min exposure. These findings indicate that some, but not all, of the actions of phorbol dibutyrate are closely associated with the translocation of protein kinase C in striatal neurons in primary culture.

Animals↗
PubMed1992

Identification of a phosphodiesterase that converts inositol cyclic 1:2-phosphate to inositol 2-phosphate.

Inositol 2-phosphate (Ins(2)P) has been identified in several cell types. The cellular levels of Ins(2)P appear to be directly correlated with the levels of inositol 1:2-cyclic phosphate (cIns(1:2)P) (Ross, T. S., Wang, F. P., and Majerus, P. W. (1992) J. Biol. Chem. 267, 19919-19923). In this study we have detected an enzyme in extracts from CV-1 cells and rat cerebellum that converts cIns(1:2)P to Ins(2)P and inositol 1-phosphate. This enzyme (designated cyclic hydrolase II) is not the same protein previously designated cIns(1:2)P 2-phosphohydrolase (cyclic hydrolase I). The products, heat inactivation curves, pH optima, and metal dependence of these two activities are different, and the two activities were separated by DEAE and gel filtration chromatography. Mixing of cyclic hydrolase I with cyclic hydrolase II does not effect the activity of either. The Km of the CV-1 cyclic hydrolase II for D-cIns(1:2)P is 10 microM. The enzyme is approximately 55 kDa as estimated by gel filtration analysis in the presence of sodium chloride and 120 kDa in its absence.

Animals↗
PubMed1989

Guanosine 5'-O-(3-thiotrisphosphate) potentiates both thrombin- and platelet-derived growth factor-induced inositol phosphate release in permeabilized vascular smooth muscle cells. Signaling mechanisms distinguished by sensitivity to pertussis toxin and phorbol esters.

We compared the mechanisms by which thrombin and platelet-derived growth factor (PDGF) activate phospholipase C in cultured vascular smooth muscle cells. Thrombin caused a transient (less than 5 min) increase in inositol trisphosphate (IP3) while PDGF caused a sustained (greater than 10 min) increase. Both pertussis toxin and phorbol 12-myristate 13-acetate (PMA) inhibited the thrombin-induced increase in IP3 but neither agent affected the PDGF-induced increase in IP3. To examine the role of GTP binding (G) proteins in the activation of phospholipase C by these two hormones, GTP analogues were introduced into saponin-permeabilized cells. In the absence of hormones, guanosine 5'-O-(3-thiotrisphosphate) (GTP gamma S) caused a progressive increase in IP3 release which was inhibited 55% by PMA (200 ng/ml). In the presence of thrombin, GTP gamma S caused synergistic increase in IP3 release. The synergism between GTP gamma S and thrombin was virtually eliminated by 10 min prior exposure to PMA (200 ng/ml). When PDGF was the hormonal agonist, GTP gamma S also caused synergistic increase in IP3 release and guanosine 5'-O-(2-thiodiphosphate) blunted PDGF-induced IP3 release. However, in contrast to thrombin, the synergism between GTP gamma S and PDGF was unaffected by PMA. Thus, thrombin and PDGF activate phospholipase C by signal transduction systems which differ in kinetic properties and in sensitivity to PMA and pertussis toxin. Despite these differences, both systems appear to involve GTP binding proteins at some step.

Animals↗
PubMed1998

Gonadotropin-releasing hormone receptors with intracellular carboxyl-terminal tails undergo acute desensitization of total inositol phosphate production and exhibit accelerated internalization kinetics.

The mammalian gonadotropin-releasing hormone receptor (GnRH-R) is the only G-protein-coupled receptor (GPCR) in which the intracellular C-terminal tail is completely absent. In contrast to other GPCRs, the GnRH-R does not show rapid desensitization of total inositol (IP) production, and the rates of internalization are exceptionally slow. We investigated whether the incorporation of a cytoplasmic tail into the C terminus of the GnRH-R affects desensitization events and receptor internalization rates. A GnRH-R/TRH-R chimera was created where the intracellular tail of the rat thyrotropin-releasing hormone receptor (TRH-R) was engineered into the C terminus of the rat GnRH-R. Three different rat GnRH-R cDNA stop codon mutations (one for each reading frame) were also made. The GnRH-stimulated IP production of the wild-type rat GnRH-R expressed in either COS-7 or HEK 293 cells did not desensitize even after prolonged stimulation with GnRH. In contrast, the catfish GnRH-R (which does possess an intracellular tail) and the TRH-R rapidly (<10 min) desensitized following agonist stimulation. The GnRH-R/TRH-R chimera also desensitized following treatment with GnRH, resembling the pattern shown by the TRH-R and the catfish GnRH-R. Two of the stop codon mutants did not show desensitization of IP production, and the third mutant with the longest tail was not functional. Internalization experiments showed that the rat GnRH-R had the slowest endocytosis and recycling rates compared with the TRH-R, the catfish GnRH-R, and the chimeric GnRH/TRH-R. This study demonstrates that the addition of a functional intracellular C-terminal tail to the GnRH-R produces rapid desensitization of IP production and significantly increases internalization rates.

Amino Acid Sequence↗
PubMed1988

Determination of inositol phosphates and other biologically important anions by ion chromatography.

Ion chromatography has been applied to the simultaneous, multi-component determination of biologically important anions. More than 20 different biologically important anions were separated on high performance ion-exchange columns and detected using chemically suppressed conductivity. Application of the technique to the separation of inositol mono-, bis-, and trisphosphates shows that these compounds can be separated from the other ions tested and can be detected at concentrations that may be found in vivo. For inositol monophosphate, the conductivity was proportional to the amount of compound from less than 20 pmol to more than 400 nmol. Although alternative methods are available for assaying each of these anions individually, the advantages of ion chromatography lie in the sensitivity of detection, the speed of separation, and the ability to simultaneously determine numerous ions. This method should be broadly applicable to studies of second messengers, measurements of reaction rates, and various metabolic studies.

Carboxylic Acids↗
PubMed1988

Di-O-alkylglycerol, mono-O-alkylglycerol and ceramide inositol phosphates of Leishmania mexicana mexicana promastigotes.

Three acidic unsaponifiable lipid fractions were isolated by chromatographic methods from sandfly vector stages (promastigotes) of a protozoan parasite of man, Leishmania mexicana mexicana, cultured in vitro. Fast atom bombardment mass spectrometry, fast atom bombardment collision induced tandem mass spectrometry and metabolic labeling were used to characterize these lipids as di-O-alkylphosphatidyl-inositols, lyso-1-O-alkylphosphatidylinositols and inositol phosphosphingolipids. Molecular species of the dialkyl forms, new to natural product biochemistry, had a 20:0 substituent and either 17:1 or 18:1. The monoalkyl forms had either 17:0 or 18:0. The predominant ceramide had the 16:1 base and the lesser component the 16:0 base. In both, the N-acyl group was 18:0.

Animals↗