Background: G-protein activation mediates inhibition of N-type Ca2+ currents. Volatile anesthetics affect G-protein pathways at various levels, and activation of G-proteins has been shown to increase the volatile anesthetic potency for inhibiting the electrical-induced contraction in ileum. The authors investigated whether isoflurane inhibition of N-type Ba2+ currents was mediated by G-protein activation.
Methods: N-type Ba2+ currents were measured in the human neuronal SH-SY5Y cell line by using the whole cell voltage-clamp method.
Results: Isoflurane was found to have two effects on N-type Ba2+ currents. First, isoflurane reduced the magnitude of N-type Ba2+ currents to a similar extent (IC50 ~ 0.28 mm) in the absence and presence of GDP[beta]S (a nonhydrolyzable GDP analog). Interestingly, GTP[gamma]S (a nonhydrolyzable GTP analog and G-protein activator) in a dose-dependent manner reduced the isoflurane block; 120 [mu]m GTP[gamma]S completely eliminated the block of 0.3 mm isoflurane and reduced the apparent isoflurane potency by ~ 2.4 times (IC50 ~ 0.68 mm). Pretreatment with pertussis toxin or cholera toxin did not eliminate the GTP[gamma]S-induced protection against the isoflurane block. Furthermore, isoflurane reduced the magnitude of voltage-dependent G-protein-mediated inhibition of N-type Ba2+ currents, and this effect was eliminated by pretreatment with pertussis toxin or cholera toxin. 相似文献
Bulletin of Experimental Biology and Medicine - In patients with moderate-to-severe and severe psoriasis and high efficacy of therapy (PASI≥75) with signaling pathway inhibitors (apremilast,... 相似文献
Experiments on animals and clinical studies in athletes have shown a negative impact of extreme exercises on the physicochemical characteristics of biomembranes. The resultant decrease in the activity of different isoforms of the multienzymatic system of hepatic cytochrome P450 may underlie, firstly, the formation of a vicious circle of increases in the microviscosity of biomembranes and membrane-dependent processes and, secondly, the lowered resistance of athletes to chemical environmental factors, which should be borne in mind during the professional activity of high-class athletes. 相似文献
Volatile anaesthetics are known to increase leakage of calcium from the
light fraction of skeletal sarcoplasmic reticulum (L-SR) which has no
calcium release channels. To explore the role of the lipid environment, we
have examined the effect of volatile anaesthetics on calcium conductance
(gCa) of lipid membranes. Planar lipid bilayers were formed with a mixture
of synthetic phospholipids and cholesterol, resembling the composition of
SR membranes, or with lipids extracted from skeletal L-SR, gCa was
estimated by calculating the calcium transference number (tCa) using
diffusion potential measurements. Membranes formed with L- SR-extracted
lipids had a higher gCa than membranes formed with synthetic lipids.
Volatile anaesthetics increased total conductance and gCa in a
dose-dependent manner, but did not affect tCa or membrane specific
capacitance. In membranes formed with L-SR-extracted lipids, isoflurane
induced the largest increase in gCa (1260 (SEM 304) % increase, n = 4, 0.94
mmol litre-1), followed by enflurane (264 (75)%, n = 5, 1.88 mmol litre-1)
and halothane (53 (33)%, n = 5; 1.54 mmol litre-1). In membranes formed
with synthetic lipids, volatile anaesthetic-induced increases in gCa
followed the same trend but were larger. Volatile anaesthetics increased
gCa without changing the ionic selectivity of membranes. However, the
magnitude of the increase in gCa in the presence of volatile anaesthetics
cannot account for the previously observed calcium leakage from L-SR
vesicles. Therefore, the volatile anaesthetic-induced increase in calcium
leakage in L-SR vesicles must be mediated via other pathways involving
membrane proteins.
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BACKGROUND: Volatile anesthetics depress cardiac contractility, which involves inhibition of cardiac L-type calcium channels. To explore the role of voltage-dependent inactivation, the authors analyzed halothane effects on recombinant cardiac L-type calcium channels (alpha1Cbeta2a and alpha1Cbeta2aalpha2/delta1), which differ by the alpha2/delta1 subunit and consequently voltage-dependent inactivation. METHODS: HEK-293 cells were transiently cotransfected with complementary DNAs encoding alpha1C tagged with green fluorescent protein and beta2a, with and without alpha2/delta1. Halothane effects on macroscopic barium currents were recorded using patch clamp methodology from cells expressing alpha1Cbeta2a and alpha1Cbeta2aalpha2/delta1 as identified by fluorescence microscopy. RESULTS: Halothane inhibited peak current (I(peak)) and enhanced apparent inactivation (reported by end pulse current amplitude of 300-ms depolarizations [I300]) in a concentration-dependent manner in both channel types. alpha2/delta1 coexpression shifted relations leftward as reported by the 50% inhibitory concentration of I(peak) and I300/I(peak)for alpha1Cbeta2a (1.8 and 14.5 mm, respectively) and alpha1Cbeta2aalpha2/delta1 (0.74 and 1.36 mm, respectively). Halothane reduced transmembrane charge transfer primarily through I(peak) depression and not by enhancement of macroscopic inactivation for both channels. CONCLUSIONS: The results indicate that phenotypic features arising from alpha2/delta1 coexpression play a key role in halothane inhibition of cardiac L-type calcium channels. These features included marked effects on I(peak) inhibition, which is the principal determinant of charge transfer reductions. I(peak) depression arises primarily from transitions to nonactivatable states at resting membrane potentials. The findings point to the importance of halothane interactions with states present at resting membrane potential and discount the role of inactivation apparent in current time courses in determining transmembrane charge transfer. 相似文献