Author: Camello, Pedro J ; Camello-Almaraz, Cristina ; Rosado, Juan A ; Calle-Ciborro, Blanca ; Pozo, Maria J ; Santos, Francisco J ; Espin-Jaime, Teresa ; Jardin, Isaac ; Gomez-Martin, Ana

The systemic effects of physical activity are mediated by the release of IL-6 and other myokines from contracting muscle. Although the release of IL-6 from muscle has been extensively studied, the information on the cellular mechanisms is fragmentary and scarce, especially regarding the role of Ca²⁺ signals. The aim of this study was to characterize the role of the main components of Ca²⁺ signals in human skeletal muscle cells during IL-6 secretion stimulated by the Ca²⁺ mobilizing agonist ATP. Primary cultures were prepared from surgical samples, fluorescence microscopy was used to evaluate the Ca²⁺ signals and the stimulated release of IL-6 into the medium was determined using ELISA. Intracellular calcium chelator Bapta, low extracellular calcium and the Ca²⁺ channels blocker La³⁺ reduced the ATP-stimulated, but not the basal secretion. Secretion was inhibited by blockers of L-type (nifedipine, verapamil), T-type (NNC55-0396) and Orai1 (Synta66) Ca²⁺ channels and by silencing Orai1 expression. The same effect was achieved with inhibitors of ryanodine receptors (ryanodine, dantrolene) and IP3 receptors (xestospongin C, 2-APB, caffeine). Inhibitors of calmodulin (calmidazolium) and calcineurin (FK506) also decreased secretion. IL-6 transcription in response to ATP was not affected by Bapta or by the T channel blocker. Our results prove that ATP-stimulated IL-6 secretion is mediated at the post-transcriptional level by Ca²⁺ signals, including the mobilization of calcium stores, the activation of store-operated Ca²⁺ entry, and the subsequent activation of voltage-operated Ca²⁺ channels and calmodulin/calcineurin pathways.

01 May 2019·NeuropharmacologyQ2 · MEDICINE

The interaction between P2X7Rs and T-type calcium ion channels in penicillin-induced epileptiform activity

Q2 · MEDICINE

Article

Author: Ayyildiz, Mustafa ; Avci, Bahattin ; Rzayev, Emil ; Arslan, Gokhan ; Kocacan, Süleyman Emre ; Agar, Erdal

Limited information exists on the link between purinergic class P2X7 receptors (P2X7Rs) and calcium ion channels in epilepsy; no data has been reported regarding the interaction between P2X7Rs and T-type calcium ion channels in epilepsy. Thus, this study is an evaluation of the role that T-type calcium ion channels play in the effect of P2X7Rs on penicillin-induced epileptiform activity. In the first set of experiments, P2X7R agonist BzATP (at 25-, 50-, 100- and 200-μg doses), P2X7R antagonist A-438079 (at 5-, 10-, 20- and 40-μg doses) and T-type calcium ion channel antagonist, NNC-550396 were administered for electrophysiological analyses 30 min after penicillin injection (2.5 μl, 500 IU). In the second set of experiments, the effective doses of these substances were used for biochemical analyses. Malondialdehyde (MDA), advanced oxidation protein product (AOPP), glutathione (GSH), glutathione reductase (GR), glutathione peroxide (GPx), catalase (CAT) and superoxide dismutase (SOD) levels were measured in the cerebrum, cerebellum and brainstem of rats. BzATP (100 μg, icv) increased the mean frequency of epileptiform activity, whereas A-438079 (40 μg, icv) and NNC-550396 (30 μg, ic) reduced it. Both A-438079 and NNC-550396 reversed BzATP's proconvulsant action. BzATP increased lipid peroxidation and protein oxidation; it also altered other antioxidant enzymes measured in this study, which were all then reversed via A-438079 and NNC-550396, at least in the cerebrum. The electrophysiological and biochemical analysis of present study suggest that P2X7Rs and its interaction with T-type calcium ion channels play an important role in the experimental model of epilepsy.

01 Mar 2011·NatureQ1 · CROSS-FIELD

The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm

Q1 · CROSS-FIELD

Article

Author: Nachiket D. Kashikar ; Reinhard Seifert ; Ingo Weyand ; U. Benjamin Kaupp ; Christoph Brenker ; Normann Goodwin ; Timo Strünker

In the oviduct, cumulus cells that surround the oocyte release progesterone. In human sperm, progesterone stimulates a Ca(2+) increase by a non-genomic mechanism. The Ca(2+) signal has been proposed to control chemotaxis, hyperactivation and acrosomal exocytosis of sperm. However, the underlying signalling mechanism has remained mysterious. Here we show that progesterone activates the sperm-specific, pH-sensitive CatSper Ca(2+) channel. We found that both progesterone and alkaline pH stimulate a rapid Ca(2+) influx with almost no latency, incompatible with a signalling pathway involving metabotropic receptors and second messengers. The Ca(2+) signals evoked by alkaline pH and progesterone are inhibited by the Ca(v) channel blockers NNC 55-0396 and mibefradil. Patch-clamp recordings from sperm reveal an alkaline-activated current carried by mono- and divalent ions that exhibits all the hallmarks of sperm-specific CatSper Ca(2+) channels. Progesterone substantially enhances the CatSper current. The alkaline- and progesterone-activated CatSper current is inhibited by both drugs. Our results resolve a long-standing controversy over the non-genomic progesterone signalling. In human sperm, either the CatSper channel itself or an associated protein serves as the non-genomic progesterone receptor. The identification of CatSper channel blockers will greatly facilitate the study of Ca(2+) signalling in sperm and help to define further the physiological role of progesterone and CatSper.

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