The defects identified in the mechanical activity of the hearts from type 1 diabetic animals include alteration of Ca 2؉ signaling via changes in critical processes that regulate intracellular Ca 2؉ concentration. These defects result partially from a dysfunction of cardiac ryanodine receptor calcium release channel (RyR2). The present study was designed to determine whether the properties of the Ca 2؉ sparks might provide insight into the role of RyR2 in the altered Ca 2؉ signaling in cardiomyocytes from diabetic animals when they were analyzed together with Ca 2؉ transients. Basal Ca 2؉ level as well as Ca 2؉ -spark frequency of cardiomyoctes isolated from 5-week streptozotocin (STZ)-induced diabetic rats significantly increased with respect to aged-matched control rats. Ca 2؉ transients exhibited significantly reduced amplitude and prolonged time courses as well as depressed Ca 2؉ loading of sarcoplasmic reticulum in diabetic rats. Spatio-temporal properties of the Ca 2؉ sparks in cardiomyocytes isolated from diabetic rats were also significantly altered to being almost parallel to the changes of Ca 2؉ transients. In addition, RyR2 from diabetic rat hearts were hyperphosphorylated and protein levels of both RyR2 and FKBP12.6 depleted. These data show that STZ-induced diabetic rat hearts exhibit altered local Ca 2؉ signaling with increased basal Ca 2؉ level.
The purinergic rP2X7 receptor expressed in a number of heterologous systems not only functions as a cation channel but also gives rise to a P2Z‐like response, i.e. a reversible membrane permeabilization that allows the passage of molecules with molecular masses of ≥300 Da. We investigated the properties of rP2X7 receptors expressed in Xenopus oocytes. In two‐electrode voltage‐clamp experiments, ATP or BzATP caused inward currents that were abolished or greatly diminished when NMDG+ or choline+ replaced Na+ as the principal external cation. In fluorescent dye experiments, BzATP application did not result in entry of the fluorophore YO‐PRO‐12+. Thus, rP2X7 expression in Xenopus oocytes does not by itself give rise to the pore‐forming P2Z phenotype, suggesting that ancillary factors are involved.
It is proposed that Zn(2+) release during the cardiac cycle results mostly from intracellular free Ca(2+) increase, triggering production of reactive oxygen species that induce changes in metal-binding properties of metallothioneins and other redox-active proteins, aside from ionic exchange on these proteins.
Racemic albuterol has been one of the most widely used beta2-adrenoceptor agonists for the relief of the symptoms of asthma, yet the use of beta2 agonists has been known to induce bronchial hyperresponsiveness. To probe a possible role of the S-enantiomer for hyperresponsiveness, we determined the effects of (S)-albuterol on intracellular Ca2+ concentration ([Ca2+]i) in dissociated bovine tracheal smooth muscle cells. Both (S)-and (R,S)-albuterol increased [Ca2+]i at concentrations of >10 pM and 1 nM, respectively, with a maximal response by 150 and 100 nM, respectively. (S)-Albuterol (1 and 10 muM) induced Ca2+ oscillations, reaching 1-2 muM [Ca2+]i. This response is in a stark contrast to that of (R)-albuterol, which decreased [Ca2+]i. The increase in [Ca2+]i was blocked by 100 nM atropine or 500 nM 4-diphenylacetoxy-N-methylpiperidine but was insensitive to the beta2 antagonist ICI 118,551 (10 muM). (S)-Albuterol (10 muM) increased inositol-1,4,5-trisphosphate levels by 213 +/- 34.4% (p < 0.05, four experiments) in cells exposed for 30 sec. The sustained phase of the Ca2+ increase was absent in Ca2+-free solution, suggesting that Ca2+ influx was responsible for the sustained Ca2+ response. The results also suggest that (S)-albuterol may cross-react with muscarinic receptors. As a Ca2+ agonist in airway smooth muscle, (S)-albuterol may have profound clinical implications because 50% of prescribed racemic albuterol is composed of (S)-albuterol.
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