PubMed · 5778533
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F Kuhlencordt. 1969-02-20. [Hyper- and hypoparathyroidism].. https://pubmed.ncbi.nlm.nih.gov/5778533/
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Stimulation of human gingival fibroblasts with histamine elicited an increase in the intracellular concentration of free calcium ([Ca2+]i) and the formation of inositol 1,4,5-trisphosphate (InsP3) in a concentration- and time-dependent manner. The histamine-induced increase in [Ca2+]i was attenuated completely by chlorpheniramine, an H1 antagonist, but not by cimetidine, an H2 antagonist. The histamine-induced Ca2+ response consisted of an initial transient peak response and a subsequent sustained increase. The transient phase can be largely attributed to Ca2+ release from intracellular InsP3-sensitive stores since the increased [Ca2+]i effect of histamine completely disappeared after depletion of intracellular Ca2+ stores with thapsigargin in the absence of extracellular Ca2+. The sustained phase was due to Ca2+ influx which was attenuated in the absence of extracellular Ca2+. The Ca2+ influx required the continuous binding of histamine to the receptor, since chlorpheniramine attenuated the increase in [Ca2+]i observed when extracellular Ca2+ was re-applied to the cells after stimulation with histamine in the absence of extracellular Ca2+. Pretreatment with the Ca2+ channel blocker SK&F96365 inhibited the Ca2+ influx component, suggesting that histamine stimulates Ca2+ influx through an H1 receptor-operated Ca2+ channel. Histamine also evoked a concentration- and time-dependent release of prostaglandin E2 (PGE2). The histamine-evoked PGE2 release was reduced markedly by exclusion of extracellular Ca2+ or pretreatment with SK&F96365 or an H1 antagonist. These results indicate that histamine stimulates both the intracellular Ca2+ release from InsP3-sensitive stores and the H1 receptor-operated Ca2+ influx from extracellular sites. The increased [Ca2+]i due to the Ca2+ influx causes PGE2 release in human gingival fibroblasts.
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Point mutagenesis, phosphatidylinositol (PI), and phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis assays and equilibrium centrifugation PIP2 assays were used to study the functional roles of four highly conserved arginine residues in the Y region of human phospholipase C delta1 (PLCdelta1) (Arg-527, -549, -556, -701). Most of the mutant enzymes were either partially defective or fully active in their abilities to catalyze the hydrolysis of PI or PIP2. However, upon substitution of Arg-549 by glycine or histidine, the mutant enzyme was defective in its ability to catalyze the hydrolysis of PIP2, but it is still able to hydrolyze PI. Replacing Arg-549 with lysine had little effect on the level of PI and PIP2 hydrolytic activities of the mutant enzyme. The residual PIP2 hydrolyzing activity of R549H is highly dependent on pH. R549H showed 5-10% of the PIP2-hydrolyzing activity of the native enzyme between pH 5 and 7 and nondetectable PIP2-hydrolyzing activity at pH 8. The PIP2-hydrolyzing activity of R549G was not detectable at all pH values. Kinetic analysis of PLCdelta1-catalyzed PIP2 hydrolysis revealed that the micellar dissociation constant Ks and interfacial Michaelis constant Km were similar in the native, R549K, and R549H enzymes; but the specific activity at the saturated substrate mole fraction and infinite level of substrate (Vmax) of the R549H mutant were reduced by a factor of 15. PIP2 competitively inhibits the native enzyme to hydrolyze PI at both pH 7 and 8. However, PIP2 inhibits R549H only at pH 7.0 and does not inhibit R549G at either pH. Taken together, these results suggest that positive charge at position 549 of PLCdelta1 protein is essential for the enzyme to recognize and catalyze the hydrolysis of PIP2 but not PI.