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Agonist Activation (agonist + activation)
Selected AbstractsAgonist activation of arachidonate-regulated Ca2+ -selective (ARC) channels in murine parotid and pancreatic acinar cellsTHE JOURNAL OF PHYSIOLOGY, Issue 3 2005Olivier Mignen ARC channels (arachidonate-regulated Ca2+ -selective channels) are a novel type of highly Ca2+ -selective channel that are specifically activated by low concentrations of agonist-induced arachidonic acid. This activation occurs in the absence of any depletion of internal Ca2+ stores (i.e. they are ,non-capacitative'). Previous studies in HEK293 cells have shown that these channels provide the predominant pathway for the entry of Ca2+ seen at low agonist concentrations where oscillatory [Ca2+]i signals are typically produced. In contrast, activation of the more widely studied store-operated Ca2+ channels (e.g. CRAC channels) is only seen at higher agonist concentrations where sustained ,plateau-type'[Ca2+]i responses are observed. We have now demonstrated the presence of ARC channels in both parotid and pancreatic acinar cells and shown that, again, they are specifically activated by the low concentrations of appropriate agonists (carbachol in the parotid, and both carbachol and cholecystokinin in the pancreas) that are associated with oscillatory [Ca2+]i signals in these cells. Uncoupling the receptor-mediated activation of cytosolic phospholipase A2 (cPLA2) with isotetrandrine reduces the activation of the ARC channels by carbachol and, correspondingly, markedly inhibits the [Ca2+]i signals induced by low carbachol concentrations, whilst those signals seen at high agonist concentrations are essentially unaffected. Interestingly, in the pancreatic acinar cells, activation by cholecystokinin induces a current through the ARC channels that is only approximately 60% of that seen with carbachol. This is consistent with previous reports indicating that carbachol-induced [Ca2+]i signals in these cells are much more dependent on Ca2+ entry than are the cholecystokinin-induced responses. [source] Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000Oleg V. Anichtchik Abstract Parkinson's disease is a major neurological disorder that primarily affects the nigral dopaminergic cells. Nigral histamine innervation is altered in human postmortem Parkinson's disease brains. However, it is not known if the altered innervation is a consequence of dopamine deficiency. The aim of the present study was to investigate possible changes in the H3 receptor system in a well-characterized model of Parkinson's disease , the 6-hydroxydopamine (6-OHDA) lesioned rats. Histamine immunohistochemistry showed a minor increase of the fibre density index but we did not find any robust increase of histaminergic innervation in the ipsilateral substantia nigra on the lesioned side. In situ hybridization showed equal histidine decarboxylase mRNA expression on both sides in the posterior hypothalamus. H3 receptors were labelled with N-alpha-[3H]-methyl histamine dihydrochloride ([3H] NAMH). Upregulation of binding to H3 receptors was found in the substantia nigra and ventral aspects of striatum on the ipsilateral side. An increase of GTP-,-[35S] binding after H3 agonist activation was found in the striatum and substantia nigra on the lesioned side. In situ hybridization of H3 receptor mRNA demonstrated region-specific mRNA expression and an increase of H3 receptor mRNA in ipsilateral striatum. Thus, the histaminergic system is involved in the pathological process after 6-OHDA lesion of the rat brain at least through H3 receptor. On the later stages of the neurotoxic damage, less H3 receptors became functionally active. Increased H3 receptor mRNA expression and binding may, for example, modulate GABAergic neuronal activity in dopamine-depleted striatum. [source] Nicotinic ,5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbersJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Robert W. B. Brown Abstract Neuronal nicotinic acetylcholine receptor subunit ,5 mRNA is widely expressed in the CNS. An ,5 gene polymorphism has been implicated in behavioral differences between mouse strains, and ,5-null mutation induces profound changes in mouse acute responses to nicotine. In this study, we have examined the distribution and prevalence of ,5* nicotinic acetylcholine receptor in mouse brain, and quantified the effects of ,5-null mutation on pre-synaptic nicotinic acetylcholine receptor function (measured using synaptosomal 86Rb+ efflux) and overall [125I]epibatidine binding site expression. ,5* nicotinic acetylcholine receptor expression was found in nine of fifteen regions examined, although < 20% of the total nicotinic acetylcholine receptor population in any region contained ,5. Deletion of the ,5 subunit gene resulted in localized loss of function (thalamus, striatum), which was itself confined to the DH,E-sensitive receptor population. No changes in receptor expression were seen. Consequently, functional changes must occur as a result of altered function per unit of receptor. The selective depletion of high agonist activation affinity sites results in overall nicotinic function being reduced, and increases the overall agonist activation affinity. Together, these results describe the receptor-level changes underlying altered behavioral responses to nicotine in nicotinic acetylcholine receptor ,5 subunit-null mutants. [source] Platelet function in sepsisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2004A. YAGUCHI Summary.,Background: Coagulation abnormalities and thrombocytopenia are common in severe sepsis, but sepsis-related alterations in platelet function are ill-defined. Objectives: The purpose of this study was to elucidate the effect of sepsis on platelet aggregation, adhesiveness, and growth factor release. Patients and methods: Agonist-induced platelet aggregation was measured in platelet-rich plasma separated from blood samples collected from 47 critically ill patients with sepsis of recent onset. Expression of platelet adhesion molecules was measured by flow cytometry and the release of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) was measured by ELISA in the supernatant of platelet aggregation. Results: Septic patients had consistently decreased platelet aggregation compared with controls, regardless of the platelet count, thrombin generation, or overt disseminated intravascular coagulation (DIC) status. The severity of sepsis correlated to the platelet aggregation defect. Adhesion molecules, receptor expression (CD42a, CD42b, CD36, CD29, PAR-1), and ,-granule secretion detected by P-selectin expression remained unchanged but the release of growth factors was differentially regulated with increased VEGF and unchanged PDGF after agonist activation even in uncomplicated sepsis. Conclusions: Sepsis decreases circulating platelets' hemostatic function, maintains adhesion molecule expression and secretion capability, and modulates growth factor production. These results suggest that sepsis alters the hemostatic function of the platelets and increases VEGF release in a thrombin-independent manner. [source] | ||||||||||