VIP and histamine H2 receptor activity in human fetal gastric glands

Summary Vasoactive intestinal peptide (VIP, EC₅₀=6.4×10^–10 M) and histamine (EC₅₀=3×10^–6 M) activated the cyclic AMP generating system in gastric glands isolated from two human fetuses at 23 weeks gestation. Histamine antagonism by the H₂ receptor blockers cimetidine (Ki=0.35×10^–6 M) and ranitidine (ki=0.51×10^–7 M) clearly characterized the histaminic activation as being of the H₂ type. It is suggested that these two vasoactive hormones may operate as neurocrine/paracrine regulators of the differentiation and/or function of the human gastric mucosa in utero.     

Feeding induced by blockade of histamine H1-receptor in rat brain

Summary Histamine antagonists were infused into the third ventricle of the cerebrum in rats. All the H₁-, but none of the H₂-antagonists tested, induced initial feeding during the early portion of the light phase when histamine level was highest. No periprandial drinking was observed. Ambulation increased during feeding. The effect on feeding was attenuated when brain histamine was normally low during the early portion of the dark phase, or was decreased by -fluoromethylhistidine. Hypothalamic neuronal histamine may suppress food intake through H₁-receptors, and diurnal fluctuations of food intake may mirror neuronal histamine levels.     

The innate immunity of the central nervous system in chronic pain: The role of Toll-like receptors

Toll-like receptors (TLRs) are a family of pattern recognition receptors that mediate innate immune responses to stimuli from pathogens or endogenous signals. Under various pathological conditions, the central nervous system (CNS) mounts a well-organized innate immune response, in which glial cells, in particular microglia, are activated. Further, the innate immune system has emerged as a promising target for therapeutic control of development and persistence of chronic pain. Especially, microglial cells respond to peripheral and central infection, injury, and other stressor signals arriving at the CNS and initiate a CNS immune activation that might contribute to chronic pain facilitation. In the orchestration of this limited immune reaction, TLRs on microglia appear to be most relevant in triggering and tailoring microglial activation, which might be a driving force of chronic pain. New therapeutic approaches targeting the CNS innate immune system may achieve the essential pharmacological control of chronic pain. Received 21 November 2006; received after revision 8 January 2007; accepted 7 February 2007     

Role of calcium in the histamine release induced by D-galactosamine from rat mast cells

Summary Rat peritoneal mast cells were isolated and purified by differential centrifugation in Ficoll. Cells pooled from three to four rats were suspended at approximately 10⁶ cells/ml in a buffered salt solution and incubated for 1 h at 37°C in 300 l volumes in the absence or presence (9×10^–4 M) of calcium chloride. Addition of D-galactosamine hydrochloride (DGM; 2.8×10^–4 M) caused (in addition to basal release) a mean ±SEM percent histamine release of 15.7±5.2 in the presence of Ca⁺⁺ and 19±4.9 in the absence of Ca⁺⁺ (p>0.05). It is suggested that D-galactosamine does not require extracellular Ca⁺⁺ for the release of histamine from the rat mast cell.A preliminary analysis of these results was presented at the International Symposium on calcium entry blockers and tissue protection, Rome, 15–16 March 1984.     

The in vitro characterization of the inhibition of mouse brain protein kinase-C by retinoids and their receptors

Summary The mechanism of the in vitro inhibition of Ca²⁺-, phosphatidylserine-dependent protein kinase C (PK-C)² by the purifiedholo (ligand-saturated) forms of cellular retinol-binding protein (cRBP) and cellular retinoic acid-binding protein (cRABP) was studied. We report here that i) the PK-C-inhibitory action ofholo-cRBP andholo-cRABP is due to their respective ligands, all-trans-retinol and all-trans-retinoic acid; ii) the reduced phosphorylation of theholo-retinoid-binding proteins and brain cytosolic proteins is not the result of a retinoid-induced soluble phosphatase or protease activity; iii) retinoids reduce PK-C affinity for calcium and phosphatidylserine in vitro; and iv) the structure-function activity of the retinoids and the specific interaction of these effect of retinoids on plasma membrane-associated PK-C activity pays a significant role in defining the early epigenetic aspects of PK-C-dependent tumor promotion and may be a physiological mechanism by which retinoids induce terminal differentiation in cell types that do not express soluble retinoid-binding proteins.We would like to thank Dr L.M. De Luca (NIH, USA) for his contribution of retinylphosphate, Dr H.N. Bhagavan (Hoffmann-La Roche) for his contribution of the arotinoids, and Merrill-Dow Corp. for their contribution of difluoromethylornithine. This work was supported by NIH Grants CA-34968, CA-07175, CA-22484, and CA-09020.     

Regulation of nicotinic acetylcholine receptors by tyrosine kinases in the peripheral and central nervous system: same players, different roles

Nicotinic acetylcholine receptors (nAChRs) exist in many subtypes and are found in the peripheral and central nervous system where they mediate or modulate synaptic transmission. We review how tyrosine phosphorylation and kinases regulate muscle and neuronal nAChRs. Interestingly, although some of the same kinase players interact with the various receptor subtypes, the functional consequences are different. While concerted action of MuSK, Abl- and Src-family kinases (SFKs) regulates the synaptic distribution of nAChRs at the neuromuscular junction, SFKs activate heteromeric neuronal nAChRs in adrenal chromaffin cells, thereby enhancing catecholamine secretion. In contrast, the activity of homomeric neuronal nAChRs, as found in the hippocampus, is negatively regulated by tyrosine phosphorylation and SFKs. It appears that tyrosine kinases provide the means to regulate all nAChRs; but the functional consequences, even those caused by the same kinase family, are specific for each receptor subtype and location. Received 21 February 2006; received after revision 24 July 2006; accepted 30 August 2006     

Ikaros negatively regulates inducible nitric oxide synthase expression in macrophages: Involvement of Ikaros phosphorylation by casein kinase 2

Ikaros is known as a critical regulator of lymphocyte development. We examined the regulatory role of Ikaros in LPS/IFN-gamma-induced inducible nitric oxide synthase (iNOS) expression by macrophages. Our results showed that IK6 (Ikaros dominant negative isoform) induction increases the iNOS expression. Ikaros DNA binding activity on the iNOS promoter was decreased, and a mutation of the Ikaros-binding site on the iNOS promoter resulted in an increase in LPS/IFN-gamma-induced iNOS expression. LPS/IFN-gamma increased the histone (H3) acetylation on the Ikaros DNA binding site. These results suggest that Ikaros acts as a negative regulator on iNOS expression. Treatment with a casein kinase 2 (CK2) inhibitor reversed LPS/IFN-gamma-induced decrease in Ikaros DNA binding activity. Moreover, overexpression of kinase-inactive CK2 decreased iNOS expression and a significant amount of CK2alpha1 translocated into the nucleus in LPS/IFN-gamma-treated cells. Overall, these data indicate that LPS/IFN-gamma decreases the Ikaros DNA binding activity via the CK2 pathway, resulting in an increase of iNOS expression.     

Role of adenosine A1 and A2 receptors in the regulation of aldosterone production in rat adrenal glands

Summary To investigate the roles of adenosine A₁ and A₂ receptors in the regulation of aldosterone production, we examined the effects of adenosine and adenosine agonists (N⁶-cyclohexyl adenosine; selective adenosine A₁ receptor agonist and 5-N-ethylcarboxamine adenosine; selective adenosine A₂ receptor agonist) on aldosterone and cyclic AMP production in rat adrenal capsular cells. Neither adenosine nor 5-N-ethylcarboxamine adenosine caused significant effects on basal aldosterone or cyclic AMP production. Also, adenosine (10^–3M) showed no consistent effects on aldosterone and cyclic AMP production induced by ACTH. On the other hand, N⁶-cyclohexyl adenosine exhibited a significant inhibition of basal aldosterone and cyclic AMP production at doses of 10^–4 M and 10^–3 M; furthermore, 10^–3 M N⁶-cyclohexyl adenosine inhibited aldosterone and cyclic AMP production stimulated by ACTH. These results suggest that adenosine A₁ receptors are coupled to and inhibit adenylate cyclase and may be involved in the inhibition of aldosterone production.