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2.
In spinal cord synaptosomes, the spider toxin PhTx3-4 inhibited capsaicin-stimulated release of glutamate in both calcium-dependent
and -independent manners. In contrast, the conus toxins, ω-conotoxin MVIIA and ω-conotoxin MVIIC, only inhibited calcium-dependent
glutamate release. PhTx3-4, but not ω-conotoxin MVIIA or ω-conotoxin MVIIC, is able to inhibit the uptake of glutamate by
synaptosomes, and this inhibition in turn leads to a decrease in the Ca 2+-independent release of glutamate. No other polypeptide toxin so far described has this effect. PhTx3-4 and ω-conotoxins MVIIC
and MVIIA are blockers of voltage-dependent calcium channels, and they significantly inhibited the capsaicin-induced rise
of intracellular calcium [Ca 2+] i in spinal cord synaptosomes, which likely reflects calcium entry through voltage-gated calcium channels. The inhibition of
the calcium-independent glutamate release by PhTx3-4 suggests a potential use of the toxin to block abnormal glutamate release
in pathological conditions such as pain. 相似文献
3.
We report on the role of K + currents in the mechanisms regulating the proliferation of UMR 106-01 osteoblastic osteosarcoma cells. Electrophysiological
analysis showed that UMR 106-01 cells produce robust K + currents that can be pharmacologically separated into two major components: a E-4031-susceptible current, I
E-4031, and a tetraethylammonium (TEA)-susceptible component, I
TEA. Western blot and RT-PCR analysis showed that I
E-4031 is produced by ether a go-go (eag)-related channels (ERG). Incubation of the cells with E-4031 enhanced their proliferation by 80%. Application of E-4031 in
the bath solution did not induce instantaneous changes in the membrane resting potential or in the level of cytosolic calcium;
however, the cells were slightly depolarized and the calcium content was significantly increased upon prolonged incubation
with the compound. Taken together these findings indicate that ERG channels can impair cell proliferation. This is a novel
finding that underscores new modes of regulation of mitosis by voltage-gated K + channels and provides an unexpected insight into the current view of the mechanisms governing bone tissue proliferation. 相似文献
4.
The metabolite of vitamin A, retinoic acid (RA), is known to affect synaptic plasticity in the nervous system and to play an important role in learning and memory. A ubiquitous mechanism by which neuronal plasticity develops in the nervous system is through modulation of voltage-gated Ca 2+ (Ca V) and voltage-gated K + channels. However, how retinoids might regulate the activity of these channels has not been determined. Here, we show that RA modulates neuronal firing by inducing spike broadening and complex spiking in a dose-dependent manner in peptidergic and dopaminergic cell types. Using patch-clamp electrophysiology, we show that RA-induced complex spiking is activity dependent and involves enhanced inactivation of delayed rectifier voltage-gated K + channels. The prolonged depolarizations observed during RA-modulated spiking lead to an increase in Ca 2+ influx through Ca V channels, though we also show an opposing effect of RA on the same neurons to inhibit Ca 2+ influx. At physiological levels of Ca 2+, this inhibition is specific to Ca V2 (not Ca V1) channels. Examining the interaction between the spike-modulating effects of RA and its inhibition of Ca V channels, we found that inhibition of Ca V2 channels limits the Ca 2+ influx resulting from spike modulation. Our data thus provide novel evidence to suggest that retinoid signaling affects both delayed rectifier K + channels and Ca V channels to fine-tune Ca 2+ influx through Ca V2 channels. As these channels play important roles in synaptic function, we propose that these modulatory effects of retinoids likely contribute to synaptic plasticity in the nervous system. 相似文献
5.
Normal vision depends on the correct function of retinal neurons and glia and it is impaired in the course of diabetic retinopathy. Müller cells, the main glial cells of the retina, suffer morphological and functional alterations during diabetes participating in the pathological retinal dysfunction. Recently, we showed that Müller cells express the pleiotropic protein potassium channel interacting protein 3 (KChIP3), an integral component of the voltage-gated K + channels K V4. Here, we sought to analyze the role of KChIP3 in the molecular mechanisms underlying hyperglycemia-induced phenotypic changes in the glial elements of the retina. The expression and function of KChIp3 was analyzed in vitro in rat Müller primary cultures grown under control (5.6 mM) or high glucose (25 mM) (diabetic-like) conditions. We show the up-regulation of KChIP3 expression in Müller cell cultures under high glucose conditions and demonstrate a previously unknown interaction between the K V4 channel and KChIP3 in Müller cells. We show evidence for the expression of a 4-AP-sensitive transient outward voltage-gated K + current and an alteration in the inactivation of the macroscopic outward K + currents expressed in high glucose-cultured Müller cells. Our data support the notion that induction of KChIP3 and functional changes of K V4 channels in Müller cells could exert a physiological role in the onset of diabetic retinopathy. 相似文献
6.
This study examines the mechanism of action of ketamine, a dissociative anesthetic, with a specific focus on its ability to inhibit changes in the concentration of intracellular free calcium, [Ca 2+] i, in PC-12 cells. The resting [Ca 2+] i as measured with the fluorescent probe Fura-2 AM in control cells is 184.8±8.6 nM (mean±SEM, n = 15). Changes in [Ca 2+] i via influx through voltage-gated calcium channels after membrane depolarization with potassium chloride were monitored in the absence and presence of various concentrations of ketamine. Potassium-depolarization caused a dose-dependent rapid increase in [Ca 2+] i, averaging 62±5%, 33±2% and 18±3% (n = 10 each) above control levels for 70 mM, 50 mM and 35 mM KCl, respectively. Ketamine, in the dosage range studied (5 – 500 μM), inhibited the increase in [Ca 2+] i stimulated by potassium-depolarization in a dose-dependent manner. The computer-fitted dose-response curve of the pooled data yielded a half maximal suppression concentration, ED 50, of 33 μM. In conclusion, this study demonstrates that ketamine inhibits Ca 2+ influx through voltage-gated Ca 2+ channels in PC-12 cells at clinically relevant doses, and may play a role in ketamine's action as a general anesthetic agent. 相似文献
7.
Neuronal voltage-gated calcium channels play a pivotal role in the conversion of electrical signals into calcium entry into nerve endings that is required for the release of neurotransmitters. They are under the control of a number of cellular signaling pathways that serve to fine tune synaptic activities, including G-protein coupled receptors (GPCRs) and the opioid system. Besides modulating channel activity via activation of second messengers, GPCRs also physically associate with calcium channels to regulate their function and expression at the plasma membrane. In this mini review, we discuss the mechanisms by which calcium channels are regulated by classical opioid and nociceptin receptors. We highlight the importance of this regulation in the control of neuronal functions and their implication in the development of disease conditions. Finally, we present recent literature concerning the use of novel μ-opioid receptor/nociceptin receptor modulators and discuss their use as potential drug candidates for the treatment of pain. 相似文献
9.
Calcium is important in controlling nuclear gene expression through the activation of multiple signal-transduction pathways in neurons. Compared with other voltage-gated calcium channels, Ca V1 channels demonstrate a considerable advantage in signalling to the nucleus. In this review, we summarize the recent progress in elucidating the mechanisms involved. Ca V1 channels, already advantaged in their responsiveness to depolarization, trigger communication with the nucleus by attracting colocalized clusters of activated CaMKII (Ca 2+/calmodulin-dependent protein kinase II). Ca V2 channels lack this ability, but must work at a distance of >1 μm from the Ca V1-CaMKII co-clusters, which hampers their relative efficiency for a given rise in bulk [Ca 2+] i (intracellular [Ca 2+]). Moreover, Ca 2+ influx from Ca V2 channels is preferentially buffered by the ER (endoplasmic reticulum) and mitochondria, further attenuating their effectiveness in signalling to the nucleus. 相似文献
10.
Neuronal G protein‐gated inwardly rectifying potassium (GIRK) channels mediate the slow inhibitory effects of many neurotransmitters post‐synaptically. However, no evidence exists that supports that GIRK channels play any role in the inhibition of glutamate release by GABA B receptors. In this study, we show for the first time that GABA B receptors operate through two mechanisms in nerve terminals from the cerebral cortex. As shown previously, GABA B receptors reduces glutamate release and the Ca 2+ influx mediated by N‐type Ca 2+ channels in a mode insensitive to the GIRK channel blocker tertiapin‐Q and consistent with direct inhibition of this voltage‐gated Ca 2+ channel. However, by means of weak stimulation protocols, we reveal that GABA B receptors also reduce glutamate release mediated by P/Q‐type Ca 2+ channels, and that these responses are reversed by the GIRK channel blocker tertiapin‐Q. Consistent with the functional interaction between GABA B receptors and GIRK channels at nerve terminals we demonstrate by immunogold electron immunohistochemistry that pre‐synaptic boutons of asymmetric synapses co‐express GABA B receptors and GIRK channels, thus suggesting that the functional interaction of these two proteins, found at the post‐synaptic level, also occurs at glutamatergic nerve terminals. 相似文献
11.
We study Ca 2+ release through single and clustered IP 3 receptor channels on the ER membrane under presence of buffer proteins. Our computational scheme couples reaction-diffusion equations and a Markovian channel model and allows our investigating the effects of buffer proteins on local calcium concentrations and channel gating. We find transient and stationary elevations of calcium concentrations around active channels and show how they determine release amplitude. Transient calcium domains occur after closing of isolated channels and constitute an important part of the channel's feedback. They cause repeated openings (bursts) and mediate increased release due to Ca 2+ buffering by immobile proteins. Stationary domains occur during prolonged activity of clustered channels, where the spatial proximity of IP 3Rs produces a distinct [Ca 2+] scale (0.5-10 μM), which is smaller than channel pore concentrations (>100 μM) but larger than transient levels. While immobile buffer affects transient levels only, mobile buffers in general reduce both transient and stationary domains, giving rise to Ca 2+ evacuation and biphasic modulation of release amplitude. Our findings explain recent experiments in oocytes and provide a general framework for the understanding of calcium signals. 相似文献
12.
Recent evidences indicate the existence of an atypical D 1 dopamine receptor other than traditional D 1 dopamine receptor in the brain that mediates PI hydrolysis via activation of phospholipase C β (PLC β). To further understand the basic physiological function of this receptor in brain, the effects of a selective phosphoinositide
(PI)-linked D 1 dopamine receptor agonist SKF83959 on cytosolic free calcium concentration ([Ca 2+] i) in cultured rat prefrontal cortical astrocytes were investigated by calcium imaging. The results indicated that SKF83959
caused a transient dose-dependent increase in [Ca 2+] i. Application of D 1 receptor, but not D 2, α 1 adrenergic, 5-HT receptor, or cholinergic antagonist prevented SKF83959-induced [Ca 2+] i rise, indicating that activation of the D 1 dopamine receptor was essential for this response. Increase in [Ca 2+] i was a two-step process characterized by an initial increase in [Ca 2+] i mediated by release from intracellular stores, supplemented by influx through voltage-gated calcium channels, receptor-operated
calcium channels, and capacitative Ca 2+ entry. Furthermore, SKF83959-stimulated increase in [Ca 2+] i was abolished following treatment with a PLC inhibitor. Overall, these results suggested that activation of D 1 receptor by SKF83959 mediates a dose-dependent mobilization of [Ca 2+] i via the PLC signaling pathway in cultured rat prefrontal cortical astrocytes. 相似文献
14.
Critical events in the life cycle of malaria parasites are controlled by calcium‐dependent signalling cascades, yet the molecular mechanisms of calcium release remain poorly understood. The synchronized development of Plasmodium berghei gametocytes relies on rapid calcium release from internal stores within 10 s of gametocytes being exposed to mosquito‐derived xanthurenic acid (XA). Here we addressed the function of phosphoinositide‐specific phospholipase C (PI‐PLC) for regulating gametocyte activation. XA triggered the hydrolysis of PIP 2 and the production of the secondary messenger IP 3 in gametocytes. Both processes were selectively blocked by a PI‐PLC inhibitor, which also reduced the early Ca 2+ signal. However, microgametocyte differentiation into microgametes was blocked even when the inhibitor was added up to 5 min after activation, suggesting a requirement for PI‐PLC beyond the early mobilization of calcium. In contrast, inhibitors of calcium release through ryanodine receptor channels were active only during the first minute of gametocyte activation. Biochemical determination of PI‐PLC activity was confirmed using transgenic parasites expressing a fluorescent PIP 2/IP 3 probe that translocates from the parasite plasmalemma to the cytosol upon cell activation. Our study revealed a complex interdependency of Ca 2+ and PI‐PLC activity, with PI‐PLC being essential throughout gamete formation, possibly explaining the irreversibility of this process. 相似文献
15.
Rat melanotrophs express several types of voltage-gated and ligand-gated calcium channels, although mechanisms involved in the maintenance of the resting intracellular Ca 2+ concentration ([Ca 2+] i) remain unknown. We analyzed mechanisms regulating resting [Ca 2+] i in dissociated rat melanotrophs by Ca 2+-imaging and patch-clamp techniques. Treatment with antagonists of L-type, but not N- or P/Q-type voltage-gated Ca 2+ channels (VGCCs) as well as removal of extracellular Ca 2+ resulted in a rapid and reversible decrease in [Ca 2+] i, indicating constitutive Ca 2+ influx through L-type VGCCs. Reduction of extracellular Na + concentration (replacement with NMDG +) similarly decreased resting [Ca 2+] i. When cells were champed at –80 mV, decrease in the extracellular Na + resulted in a positive shift of the holding current. In cell-attached voltage-clamp and whole-cell current-clamp configurations, the reduction of extracellular Na + caused hyperpolarisation. The holding current shifted in negative direction when extracellular K + concentration was increased from 5 mM to 50 mM in the presence of K + channel blockers, Ba 2+ and TEA, indicating cation nature of persistent conductance. RT-PCR analyses of pars intermedia tissues detected mRNAs of TRPV1, TRPV4, TRPC6, and TRPM3-5. The TRPV channel blocker, ruthenium red, shifted the holding current in positive direction, and significantly decreased the resting [Ca 2+] i. These results indicate operation of a constitutive cation conductance sensitive to ruthenium red, which regulates resting membrane potential and [Ca 2+] i in rat melanotrophs. 相似文献
16.
Catecholamines and other transmitters released from adrenal chromaffin cells play central roles in the “fight-or-flight” response
and exert profound effects on cardiovascular, endocrine, immune, and nervous system function. As such, precise regulation
of chromaffin cell exocytosis is key to maintaining normal physiological function and appropriate responsiveness to acute
stress. Chromaffin cells express a number of different G protein coupled receptors (GPCRs) that sense the local environment
and orchestrate this precise control of transmitter release. The primary trigger for catecholamine release is Ca 2+ entry through voltage-gated Ca 2+ channels, so it makes sense that these channels are subject to complex regulation by GPCRs. In particular G protein βγ heterodimers
(Gβγ) bind to and inhibit Ca 2+ channels. Here I review the mechanisms by which GPCRs inhibit Ca 2+ channels in chromaffin cells and how this might be altered by cellular context. This is related to the potent autocrine inhibition
of Ca 2+ entry and transmitter release seen in chromaffin cells. Recent data that implicate an additional inhibitory target of Gβγ
on the exocytotic machinery and how this might fine tune neuroendocrine secretion are also discussed. 相似文献
17.
BackgroundRetinal ganglion cells expressing the photopigment melanopsin are intrinsically photosensitive (ipRGCs). These ganglion cell photoreceptors send axons to several central targets involved in a variety of functions. Within the retina ipRGCs provide excitatory drive to dopaminergic amacrine cells via glutamatergic signals and ipRGCs are coupled to wide-field GABAergic amacrine cells via gap junctions. However, the extent to which ipRGCs are coupled to other retinal neurons in the ganglion cell layer via gap junctions is unclear. Carbenoxolone, a widely employed gap junction inhibitor, greatly reduces the number of retinal neurons exhibiting non-rod, non-cone mediated light-evoked Ca 2+ signals suggesting extensive intercellular coupling between ipRGCs and non-ipRGCs in the ganglion cell layer. However, carbenoxolone may directly inhibit light-evoked Ca 2+ signals in ipRGCs independent of gap junction blockade. Methodology/Principal FindingsTo test the possibility that carbenoxolone directly inhibits light-evoked Ca 2+ responses in ipRGCs, the light-evoked rise in intracellular Ca 2+ ([Ca 2+] i) was examined using fura-2 imaging in isolated rat ipRGCs maintained in short-term culture in the absence and presence of carbenoxolone. Carbenoxolone at 50 and 100 µM concentrations completely abolished the light-evoked rise in [Ca 2+] i in isolated ipRGCs. Recovery from carbenoxolone inhibition was variable. Conclusions/SignificanceWe demonstrate that the light-evoked rise in [Ca 2+] i in isolated mammalian ganglion cell photoreceptors is inhibited by carbenoxolone. Since the light-evoked increase in [Ca 2+] i in isolated ipRGCs is almost entirely due to Ca 2+ entry via L-type voltage-gated calcium channels and carbenoxolone does not inhibit light-evoked action potential firing in ipRGCs in situ, carbenoxolone may block the light-evoked increase in [Ca 2+] i in ipRGCs by blocking L-type voltage-gated Ca 2+ channels. The ability of carbenoxolone to block evoked Ca 2+ responses must be taken into account when interpreting the effects of this pharmacological agent on retinal or other neuronal circuits, particularly if a change in [Ca 2+] i is the output being measured. 相似文献
19.
Activity of voltage-gated potassium (Kv) channels controls membrane potential, which subsequently regulates cytoplasmic free calcium concentration ([Ca 2+] cyt) in pulmonary artery smooth muscle cells (PASMCs). Acute hypoxia inhibits Kv channel function in PASMCs, inducing membrane depolarization and a rise in [Ca 2+ ] cyt that triggers vasoconstriction. Prolonged hypoxia inhibits expression of Kv channels and reduces Kv channel currents in PASMCs. The consequent membrane depolarization raises [Ca 2+] cyt, thus stimulating PASMC proliferation. The present review discusses recent evidence for the involvement of Kv channels in initiation of hypoxic pulmonary vasoconstriction and in chronic hypoxia-induced pulmonary hypertension. 相似文献
20.
Cerebellar Purkinje neurons (PNs) receive two main excitatory inputs, from climbing fibers and parallel fibers, and inhibitory inputs, from GABAergic interneurons. The synapses formed by parallel fibers and by inhibitory interneurons on PNs are able to undergo long-lasting in efficacy. Thus, the excitatory parallel fiber-PN synapse undergoes long-term fibers. Synaptic inhibition can be potentiated by climbing fiber activity by a mechanism named rebound potentiation, resulting in a more powerful inhibitory effect of GABAergic interneurons. The induction of both long-term depression and rebound potentiation requires a transient elevation of the cytoplasmic calcium concentration ([Ca 2+] i). The [Ca 2+] i-transient is caused by Ca 2+ entry through voltage-gated Ca 2+ channels and, possibly, by release of Ca 2+ from IP 3- and ryanodine-sensitive stores. Direct Ca 2+ entry through synaptic AMPA receptor channels seems not to contribute significantly to the Ca 2+ signal mediating the induction of both long-term depression and rebound potentiation. 相似文献
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