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The regulation of intracellular Ca2 + triggers a multitude of vital processes in biological cells. Ca2 + permeable ryanodine receptors (RyRs) are the biggest known ion channels and play a key role in the regulation of intracellular calcium concentrations, particularly in muscle cells. In this study, we construct a computational model of the pore region of the skeletal RyR and perform molecular dynamics (MD) simulations. The dynamics and distribution of Ca2 + around the luminal pore entry of the RyR suggest that Ca2 + ions are channeled to the pore entry due to the arrangement of (acidic) amino acids at the extramembrane surface of the protein. This efficient mechanism of Ca2 + supply is thought to be part of the mechanism of Ca2 + conductance of RyRs. Viral myocarditis is predominantly caused by coxsackie viruses that induce the expression of the protein 2B which is known to affect intracellular Ca2 + homeostasis in infected cells. From our sequence comparison, it is hypothesized, that modulation of RyR could be due to replacement of its transmembrane domains (TMDs) by those domains of the viral channel forming protein 2B of coxsackie virus. This article is part of a Special Issue entitled: Viral Membrane Proteins — Channels for Cellular Networking.  相似文献   
3.
Mitochondrial hexokinase (HK) and creatine kinase (CK) known to form complexes with a voltage dependent anion channel (VDAC) have been reported to increase cell death resistance under hypoxia/anoxia. In this work we propose a new, non-Mitchell mechanism of generation of the inner and outer membrane potentials at anaerobic conditions. The driving force is provided by the Gibbs free energy of the HK and CK reactions associated with the VDAC–HK and the ANT (adenine nucleotide translocator)–CK–VDAC complexes, respectively, both functioning as voltage generators. In the absence of oxygen, the cytosolic creatine phosphate can be directly used by the ANT–CK–VDAC contact sites to produce ATP from ADP in the mitochondrial matrix. After that, ATP released through the fraction of unbound ANTs in exchange for ADP is used in the mitochondrial intermembrane space by the outer membrane VDAC–HK electrogenic complexes to convert cytosolic glucose into glucose-6-phosphate. A simple computational model based on the application of Ohm's law to an equivalent electrical circuit showed a possibility of generation of the inner membrane potential up to − 160 mV, under certain conditions, and of relatively high outer membrane potential without wasting of ATP that normally leads to cell death. The calculated membrane potentials depended on the restriction of ATP/ADP diffusion in narrow cristae and through the cristae junctions. We suggest that high inner membrane potential and calcium extrusion from the mitochondrial intermembrane space by generated positive outer membrane potential prevent mitochondrial permeability transition, thus allowing the maintenance of mitochondrial integrity and cell survival in the absence of oxygen.  相似文献   
4.
Our previous study reported that cerebrosides from traditional Chinese medicine Baifuzi directly interact with the STREX domain of BKCa channels, which in turn results in the therapeutic effect of Baifuzi on ischemic stroke. However, it is not known how cerebrosides in the plasma membrane could interact with the STREX domain that is in the cytoplasmic side. Using patch-clamp technique, effects of different cerebrosides on the BKCa channel were studied by measuring single channel currents in CHO cells expressing wild type or mutated BKCa channels. Palmitoylation of the STREX domain was removed either by site-directed mutagenesis or pharmacological inhibition. Removal of palmitoylation sites at C646 and C647 by mutating the residues to Ala abolished the ability of cerebrosides to activate the BKCa channel. In contrast, the mutation neither changed the single channel conductance nor voltage sensitivity of the channel. Both palmitoylation inhibitors tunicamycin and palmitic acid analog 2-bromopalmitate attenuated the activation of the BKCa channel by cerebrosides. Furthermore, confocal images on STREX-EGFP fragments demonstrated that STREX fragments no longer associated with the plasma membrane when the palmitoylation was removed or blocked. These findings suggest that palmitoylation of the STREX domain is necessary for cerebrosides to activate the BKCa channel and provide insight into the mechanism of how Baifuzi could exert therapeutic effect on ischemic stroke.  相似文献   
5.
The inside-out mode of the patch-clamp technique was used to study adenosine-5-triphosphate (ATP)-sensitive K+ channels in mammalian skeletal muscle. Vanadate, applied to the cytoplasmic face of excised patches, was a potent activator of ATP-sensitive K+ channels. Divalent cations (Mg2+, Ca2+) were a prerequisite for the activating process. The maximal effect was achieved using 1 mM vanadate dissolved in Ringer, increasing the open-state probability about ninefold. The active 5 + redox form of vanadate which stimulates ATP-sensitive K+ channels is likely to be decavanadate V10O inf28 sup6– . ATP concentration-response curves have Hill coefficients near three in internal Na+-rich Ringer and between one and two in internal KCl solutions. Half maximal channel blockage was observed at ATP concentrations of 4 and 8 M in Ringer and KCl solutions, respectively. Internal vanadate shifted the curves towards higher ATP concentrations without affecting their slopes. Thus 50% channel blockage occurred at 65 M ATP in internal Ringer containing 0.5 mM vanadate. The results indicate that the affinity and stoichiometry of ATP binding to ATP-sensitive K+ channels are strongly modulated by internal cations and that the ATP sensitivity is weakened by vanadate. Offprint requests to: B. Neumcke  相似文献   
6.
Abstract: The identity and role of G proteins in coupling adenosine receptors to effectors have been studied to a limited degree. We have identified the G proteins whose GTPase activity is stimulated by adenosine receptor agonists in neuronal membranes. (R)-Phenylisopropyladenosine, 2-chloroadenosine, and N-ethylcarboxamideadenosine produced a concentration-dependent stimulation of GTPase. At 10?5M, the increase above basal GTPase in frontal cortex was 25 ± 4, 20 ± 3, and 8 ± 1%, respectively, and in the cerebellum 55 ± 2, 41 ± 4, and 22 ± 2%, respectively. The effects of (R)-phenylisopropyladenosine and 2-chloroadenosine were inhibited by (1) A1 antagonists (76–96% reduction), (2) pretreatment with pertussis toxin (90–100% reduction), and (3) antibodies raised against the α-subunit of Gi and Go (55–57% reduction by each), suggesting that A1 receptors interact equally with Gi and Go. (R)-Phenylisopropyladenosine increased the binding of a nonhydrolyzable analogue of GTP to membranes in a pertussis toxin-sensitive manner, indicative of activation of Gi or Go. Previously, (±)-Bay K 8644 enhanced GTP hydrolysis by Go but not Gi. Now we report a profound synergistic stimulation of GTPase in the presence of (R)-phenylisopropyladenosine and (±)-Bay K 8644 (10?7 to 10?5M). (±)-Bay K 8644 had no effect on nucleotide exchange and, thus, cannot activate Go. It appears that a positive cooperative stimulation of Go occurs when it is first activated by A1 receptors and subsequently interacts with the L-type Ca2+ channel.  相似文献   
7.
Summary The changes in Na current during development were studied in the dorsal root ganglion (DRG) cells using the whole-cell patch-clamp technique. Cells obtained from rats 1–3 and 5–8 days after birth were cultured and their Na currents were compared. On top of the two types of Na currents reported in these cells (fast-FA current and slow-S current) a new fast current was found (FN). The main characteristics of the three currents are: (i) The voltages of activation are –37, –36, and –23 mV for the FN, FA and S currents, respectively. (ii) The activation and inactivation kinetics of FN and FA currents are about five times faster than those of the S current. (iii) The voltages at which inactivation reaches 50% are –139, –75 and –23 mV for the FN, FA and S currents, respectively.The kinetics and voltage-dependent parameters of the three currents and their density do not change during the first eight days after birth. However, their relative frequency in the cells changes. In the 1–3 day-old rats the precent of cells with S, FA, and mixed S+FN currents is 22, 18, and 60% of the cells, respectively. In the 5–8 day-old, the percent of cells with S, FA, and FN+S is 10, 66 and 22%. The relative increase in the frequency of cells with FA current during development can contribute to the ease of action potential generation compared with cells with FN currents, which are almost completely inactivated under physiological conditions. The predominance of FA cells also results in a significant decrease in the relative frequency of cells with the high-threshold, slow current.Antibodies directed against a part of the S4 region of internal repeat I of the sodium channel (C 1 + , amino acids 210–223, eel channel numbering) were found to shift the voltage dependence of FA current inactivation (but not of FN or S currents) to more negative potentials. The effect was found only when the antibodies were applied externally. The results suggest that FN, FA and S types of Na currents are generated by channels, which are different in the topography of the C 1 + region in the membrane.  相似文献   
8.
吴庆  任俊 《生理学报》1997,49(4):407-413
本文用膜片箝技术研究了孕烯酮硫酸醌对大脑皮层锥体神经元膜48pS延迟整流型钾通道开放概率和平均开放时间的影响。在加入PS后40s,即可观察到IK通道的开放概率增大,平均开放时间延长,表明PS加强IK通道的活动。在浓度为300-100μmol/L的范围内,其增大程度与PS的浓度呈正相关,但PS不影响通道的电流幅度。  相似文献   
9.
Photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. We have shown endoplasmic reticulum (ER) stress-associated apoptotic cone death and increased phosphorylation of the ER Ca2+ channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in CNG channel-deficient mice. We also presented a remarkable elevation of cGMP and an increased activity of the cGMP-dependent protein kinase (protein kinase G, PKG) in CNG channel deficiency. This work investigated whether cGMP/PKG signaling regulates ER stress and IP3R1 phosphorylation in CNG channel-deficient cones. Treatment with PKG inhibitor and deletion of guanylate cyclase-1 (GC1), the enzyme producing cGMP in cones, were used to suppress cGMP/PKG signaling in cone-dominant Cnga3−/−/Nrl−/− mice. We found that treatment with PKG inhibitor or deletion of GC1 effectively reduced apoptotic cone death, increased expression levels of cone proteins, and decreased activation of Müller glial cells. Furthermore, we observed significantly increased phosphorylation of IP3R1 and reduced ER stress. Our findings demonstrate a role of cGMP/PKG signaling in ER stress and ER Ca2+ channel regulation and provide insights into the mechanism of cone degeneration in CNG channel deficiency.  相似文献   
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