lithium-chloride and inositol-4-phosphate

Carbamazepine (CBZ) resembles lithium in its beneficial effects in therapy and prophylaxis of affective disorders. Since lithium is presumed to act via an attenuation of the inositolphosphate/Ca(2+)-second messenger system, it is of particular interest whether or not CBZ might also have inhibitory effects on this type of signal transduction. CBZ is an antagonist of adenosine A1-receptor subtypes. We show here that activation of adenosine A1-receptors potentiates the phenylephrine induced formation of inositolphosphates in hippocampal astrocytes and that this potentiating effect is inhibited by CBZ at a therapeutically relevant concentration. These results indicate that CBZ can by antagonism of adenosine A1-receptors inhibit the inositolphosphate/Ca(2+)-signalling in neural pathways regulated by adenosine.

Topics: Adenosine; Animals; Animals, Newborn; Astrocytes; Carbamazepine; Cells, Cultured; Drug Synergism; Hippocampus; Inositol Phosphates; Lithium Chloride; Neural Pathways; Phenylephrine; Purinergic P1 Receptor Antagonists; Rats; Receptors, Purinergic P1; Second Messenger Systems; Signal Transduction

Lithium-induced hyperparathyroidism is characterized by a reduction in parathyroid sensitivity to changes in extracellular calcium (Ca2+). Ca(2+)-induced transmembrane signal transduction in the parathyroid cell is known to result in the hydrolysis of phosphatidylinositol bisphosphate (PIP2), generating increases in intracellular inositol phosphates, a process which is mediated by a calcium receptor.. To determine if lithium's effect on parathyroid cell function is mediated by an alteration in Ca(2+)-induced hydrolysis of PIP2, inositol 4-monophosphate (IP1), and inositol 1,4,5-trisphosphate (IP3) were measured using anion-exchange chromatography in normal and lithium chloride (LiCl)-treated bovine parathyroid cells at Ca2+ concentrations varying from 0.5 mmol/L to 5.0 mmol/L. IP1 and IP3 concentrations were determined in terms of percent control, defined as the IP1 or IP3 concentration at an [Ca2+] of 0.5 mmol/L.. Increases in [IP1]/10(6) cells (mean +/- standard error of the mean [SEM]) in response to progressive increases in Ca2+ from 0.5 mmol/L to 5.0 mmol/L varied from 825 +/- 228 to 4,474 +/- 382 in control cells versus 1,139 +/- 243 to 4,689 +/- 630 in cells pretreated with LiCl (P > 0.05). The increases in [IP3]/10(6) cells (mean +/- SEM) in response to increases in Ca2+ from 0.5 mmol/L to 5.0 mmol/L, varied from 146 +/- 14 to 385 +/- 35 in control cells versus 134 +/- 16 to 327 +/- 55 in cells pretreated with LiCl (P > 0.05).. Our results demonstrate that LiCl does not effect Ca(2+)-induced hydrolysis of PIP2, suggesting that the desensitizing effect of LiCl on the parathyroid cell is not the result of a Ca2+ receptor-mediated phenomenon.

Topics: Animals; Animals, Newborn; Calcium; Cattle; Cell Membrane; Cells, Cultured; Chromatography, Ion Exchange; Dose-Response Relationship, Drug; Hydrolysis; Hyperparathyroidism; Inositol 1,4,5-Trisphosphate; Inositol Phosphates; Lithium Chloride; Parathyroid Glands; Phosphatidylinositol Phosphates; Phosphatidylinositols; Signal Transduction

Phosphoinositide (PI) and calcium metabolism were studied in guinea pig cerebral cortex synaptosomes. Mass amounts of inositol and inositol monophosphates, and the levels of free intrasynaptosomal calcium ([Ca2+]i) were measured after KCl (60 mM), after a direct cholinergic agonist carbachol (CA, 1mM), and after their combination. Inositol, inositol-1-phosphate (Ins1P), inositol-4-phosphate (Ins4P) and [Ca2+]i were measured with and without 10 mM LiCl in the incubation medium. CA-induced cholinergic stimulation elevated synaptosomal Ins4P levels by 40% but did not affect Ins1P or [Ca2+]i. On the contrary, KCl elevated Ins1P by 50% and [Ca2+]i by 40% above the resting level, and decreased inositol by 20%, whereas no alterations in Ins4P occurred. CA did not modify the responses of KCl, but KCl abolished the elevation of Ins4P by CA. LiCl attenuated KCl-induced elevation of Ins1P but amplified the CA-induced elevation of Ins4P. The elevation of presynaptic [Ca2+]i was accompanied by accumulation of Ins1P but not that of Ins4P. Hence, the present results suggest that presynaptic cholinergic stimulation and KCl-induced depolarization may activate different degradation pathways of inositolphosphate metabolism.

Topics: Animals; Calcium; Carbachol; Cerebral Cortex; Chlorides; Female; Guinea Pigs; Inositol Phosphates; Lithium; Lithium Chloride; Male; Phosphatidylinositols; Potassium Chloride; Synaptosomes

Cerebral regional inositol, inositol-1-phosphate (Ins1P), and inositol-4-phosphate (Ins4P), intermediates in phosphoinositide (PI) cycle, and brain lithium levels were studied in male Han:Wistar rats 24 hr after an intraperitoneal injection of a single dose (2.5-18 mEq./kg) of LiCl. A dose of LiCl higher than 5 mEq/kg caused a remarkable accumulation of Li+ in the brain. Basal brain regional inositol levels (17-22 mmol/kg) were reduced by 6-8 mmol/kg dry brain tissue at doses exceeding 5 mEq/kg of LiCl in all brain regions except the piriform cortex. However, higher doses of LiCl did not cause any further decrease in brain inositol. LiCl increased basal brain regional Ins1P levels (170-240 mumol/kg) by 0.8 mmol/kg dry brain tissue at most, and there were no consistent additional increases of Ins1P at LiCl doses exceeding 5 mEq./kg. Moreover, lithium slightly decreased regional cerebral concentrations of Ins4P. Thus, lithium-induced accumulation of Ins1P or changes of Ins4P levels do not explain lithium-induced decrease in cerebral inositol. Effects of lithium on brain P1 turnover are likely to be multifocal and to differ markedly at different concentrations of Li+ in the brain.

Topics: Animals; Brain Chemistry; Chlorides; Inositol; Inositol Phosphates; Lithium; Lithium Chloride; Male; Mass Spectrometry; Rats; Rats, Inbred Strains

We report that there are distinct thyrotropin-releasing hormone (TRH)-responsive and -unresponsive pools of inositol (Ins) lipids in rat pituitary tumour (GH3) cells, and present evidence that the size of the responsive pool is determined by the number of activated TRH-receptor complexes. By use of an experimental protocol in which cycling of [3H]Ins is inhibited and resynthesis occurs with unlabelled Ins only, we were able to measure specifically the effects of TRH on the hydrolysis of the Ins lipids present before stimulation. A maximally effective dose of TRH (1 microM) caused a time-dependent decrease in 3H-labelled Ins lipids that attained a steady-state value of 42 +/- 1% of the initial level between 1.5 and 2 h. After 2 h, even though there was no further decrease in 3H-labelled Ins lipids, and no increase in [3H]Ins or [3H]Ins phosphates, turnover of Ins lipids, as assessed as incorporation of [32P]Pi into PtdIns, continued at a rate similar to that in cells incubated without LiCl or unlabelled Ins. These data indicate that Ins lipid turnover was not desensitized during prolonged TRH stimulation. Depletion of lipid 3H radioactivity by TRH occurred at higher TRH doses on addition of the competitive antagonist chlordiazepoxide. Addition of 1 microM-TRH after 3 h of stimulation by a sub-maximal (0.3 nM) TRH dose caused a further decrease in 3H radioactivity to the minimum level (40% of initial value). We propose that the TRH-responsive pool of Ins lipids in GH3 cells is composed of the complement of Ins lipids that are within functional proximity of activated TRH-receptor complexes.

Topics: Animals; Chlorides; Inositol; Inositol Phosphates; Kinetics; Lithium; Lithium Chloride; Phosphatidylinositols; Pituitary Neoplasms; Rats; Receptors, Neurotransmitter; Receptors, Thyrotropin-Releasing Hormone; Thyrotropin-Releasing Hormone; Tumor Cells, Cultured

1. Hydrolysis of both enantiomers of inositol 1-phosphate and both enantiomers of inositol 4-phosphate to inositol is inhibited by LiCl in liver and brain. 2. The phosphatase activity is predominantly soluble. 3. Inositol 1,4-bisphosphate is also hydrolysed by the soluble fraction of liver and brain. 4. Bisphosphatase activity is inhibited by LiCl, but is less sensitive than monophosphatase activity. 5. The product of bisphosphatase in liver and brain is inositol 4-phosphate.

Topics: Animals; Brain; Chlorides; Chromatography, High Pressure Liquid; Hydrolysis; In Vitro Techniques; Inositol; Inositol Phosphates; Lithium; Lithium Chloride; Liver; Phosphoric Monoester Hydrolases; Rats; Sugar Phosphates