Journal of receptor and signal transduction research
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J. Recept. Signal Transduct. Res. · Apr 2010
Effects of levobupivacaine and bupivacaine on intracellular calcium signaling in cultured rat dorsal root ganglion neurons.
Bupivacaine and levobupivacaine have been shown to be effective in the treatment of pain as local anesthetics, although the mechanisms mediating their antinociceptive actions are still not well understood. The aim of this study was to investigate the effects of bupivacaine and levobupivacaine on intracellular calcium ([Ca(2+)](i)) signaling in cultured rat dorsal root ganglion (DRG) neurons. DRG neuronal cultures loaded with 5 microM Fura-2/AM and [Ca(2+)](i) transients for stimulation with 30 mM KCl (Hi K(+)) were assessed by using fluorescent ratiometry. ⋯ Bupivacaine also inhibited Hi K(+)-induced [Ca(2+)](i) responses, reduced to 98.7 +/- 4.8% (n = 10) and 69.5 +/- 4.5% (n = 9, P < 0.05) inhibition of fluorescence ratio values of Hi K(+)-induced responses at 5 and 50 microM, respectively. Our results indicate that bupivacaine and levobupivacaine, with no significant differences between both agents, attenuated KCl-evoked calcium transients in a reversible manner. The inhibition of calcium signals in DRG neurons by levobupivacaine and bupivacaine might contribute to the antinociceptive effects of these local anesthetics.
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J. Recept. Signal Transduct. Res. · Jan 2006
ReviewControl of peroxisome proliferator-activated receptor fate by the ubiquitinproteasome system.
Peroxisome proliferator-activated receptor (PPAR) alpha, gamma, and delta belong to the nuclear hormone receptor superfamily of ligand-activated transcription factors. PPARs regulate metabolic, developmental, and differentiation pathways and play important roles in human diseases, such as diabetes, atherosclerosis, cancer, and chronic inflammation. PPARs are the targets of drugs of widespread clinical use and represent promising targets for discovery of new therapeutics. ⋯ The UPS plays an important role in regulating the levels and modulating ligand-dependent and-independent activity of nuclear receptors. This review highlights the current knowledge regarding the interactions of the UPS with PPARs and focuses on the differential regulation of the level and activity of the PPAR isotypes by the UPS in response to selective ligands. Understanding the connections between the UPS and PPARs can provide insights in the actions of existing drugs and raise the possibilities for development of more effective PPAR-based therapeutics.
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J. Recept. Signal Transduct. Res. · Jan 1999
Discovery and design of novel vasopressin hypotensive peptide agonists.
This presentation will trace the serendipitous discovery of novel vasopressin (VP) hypotensive agonists d(CH2)5[D-Tyr(Et)2,X3]VAVP (where X = Arg, Lys). These peptides were uncovered as part of an ongoing program aimed at the design of potent and selective VP antidiuretic (V2 receptor) antagonists. We will also present highlights of our subsequent preliminary studies seeking (i) to design high affinity radioiodinatable ligands for the localization and characterization of the putative VP vasodilatory (V1c?) receptor; (ii) to identify the structural features of selective and non-selective cyclic and linear VP and oxytocin (OT) antagonists of the V2 receptor, the vascular (V1a) receptor and of the uterine (OT) receptor required for hypotensive agonism and; (iii) to enhance hypotensive potency. These novel VP hypotensive agonists could serve as valuable research tools in studies on the roles of VP in blood pressure regulation and may also lead to the development of a new class of therapeutically useful antihypertensives.
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J. Recept. Signal Transduct. Res. · Mar 1998
[3H]5,7-dichlorokynurenic acid recognizes two binding sites in rat cerebral cortex membranes.
Binding of [3H]5,7-dichlorokynurenic acid ([3H]DCKA), a competitive antagonist of the strychnine-insensitive glycine site of the N-methyl-D-aspartate (NMDA) receptor channel complex, was characterized in synaptic plasma membranes from rat cerebral cortex. Non linear curve fitting of [3H]DCKA saturation and homologous displacement isotherms indicated the existence of two binding sites: a specific, saturable, high affinity site, with a pKD value of 7.24 (KD = 57.5 nmol/l) and a maximum binding value (Bmax) of 6.9 pmol/mg of protein and a second site, with micromolar affinity. ⋯ The low affinity component of [3H]DCKA binding was insensitive to the agonists glycine and D-serine and the partial agonist (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA 966), though recognised by glycine site antagonists. The precise nature of this second, low affinity [3H]DCKA binding site remains to be elucidated.