American journal of physiology. Cell physiology
-
Am. J. Physiol., Cell Physiol. · May 2007
Elevated resting [Ca(2+)](i) in myotubes expressing malignant hyperthermia RyR1 cDNAs is partially restored by modulation of passive calcium leak from the SR.
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered in susceptible individuals by inhalation anesthetics and depolarizing skeletal muscle relaxants. This syndrome has been linked to a missense mutation in the type 1 ryanodine receptor (RyR1) in more than 50% of cases studied to date. Using double-barreled Ca(2+) microelectrodes in myotubes expressing wild-type RyR1 ((WT)RyR1) or RyR1 with one of four common MH mutations ((MH)RyR1), we measured resting intracellular Ca(2+) concentration ([Ca(2+)](i)). ⋯ However, when myotubes were exposed to bastadin 5 alone or to a combination of ryanodine and bastadin 5, the resting [Ca(2+)](i) was significantly reduced (P < 0.01). Interestingly, the percent decrease in resting [Ca(2+)](i) in myotubes expressing (MH)RyR1s was significantly greater than that for (WT)RyR1. From these data, we propose that the high resting myoplasmic [Ca(2+)](i) in (MH)RyR1 expressing myotubes is due in part to a related structural conformation of (MH)RyR1s that favors "passive" calcium leak from the sarcoplasmic reticulum.
-
Am. J. Physiol., Cell Physiol. · May 2007
Comparative StudyMouse colon sensory neurons detect extracellular acidosis via TRPV1.
Extracellular acidification contributes to pain by activating or modulating nociceptor activity. To evaluate acidic signaling from the colon, we characterized acid-elicited currents in thoracolumbar (TL) and lumbosacral (LS) dorsal root ganglion (DRG) neurons identified by content of a fluorescent dye (DiI) previously injected into the colon wall. In 13% of unidentified LS DRG neurons (not labeled with DiI) and 69% of LS colon neurons labeled with DiI, protons activated a sustained current that was significantly and reversibly attenuated by the transient receptor potential vanilloid receptor 1 (TRPV1) antagonist capsazepine. ⋯ Similar to LS colon DRG neurons, acid-elicited currents in TL colon DRG neurons were mediated predominantly by TRPV1. However, the pH producing half-activation of responses significantly differed between TL and LS colon DRG neurons. The properties of acid-elicited currents in colon DRG neurons suggest differential contributions of ASICs and TRPV1 to colon sensation and likely nociception.
-
Am. J. Physiol., Cell Physiol. · May 2007
Isoflurane preconditioning uncouples mitochondria and protects against hypoxia-reoxygenation.
Ischemic cardiac injury can be substantially alleviated by exposing the heart to pharmacological agents such as volatile anesthetics before occurrence of ischemia-reperfusion. A hallmark of this preconditioning phenomenon is its memory, when cardioprotective effects persist even after removal of preconditioning stimulus. Since numerous studies pinpoint mitochondria as crucial players in protective pathways of preconditioning, the aim of this study was to investigate the effects of preconditioning agent isoflurane on the mitochondrial bioenergetic phenotype. ⋯ Partial mitochondrial depolarization was paralleled by a diminished Ca(2+) uptake into isoflurane-treated mitochondria, as indicated by the reduced increment in rhod-2 fluorescence when mitochondria were challenged with increased Ca(2+) (180 +/- 24 vs. 258 +/- 14% for the control). In conclusion, isoflurane preconditioning elicits partial mitochondrial uncoupling and reduces mitochondrial Ca(2+) uptake. These effects are likely to reduce the extent of the mitochondrial damage after the hypoxic stress.