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1.
Astrocytes contribute to the formation and function of synapses and are found throughout the brain, where they show intracellular store-mediated Ca(2+) signals. Here, using a membrane-tethered, genetically encoded calcium indicator (Lck-GCaMP3), we report the serendipitous discovery of a new type of Ca(2+) signal in rat hippocampal astrocyte-neuron cocultures. We found that Ca(2+) fluxes mediated by transient receptor potential A1 (TRPA1) channels gave rise to frequent and highly localized 'spotty' Ca(2+) microdomains near the membrane that contributed appreciably to resting Ca(2+) in astrocytes. Mechanistic evaluations in brain slices showed that decreases in astrocyte resting Ca(2+) concentrations mediated by TRPA1 channels decreased interneuron inhibitory synapse efficacy by reducing GABA transport by GAT-3, thus elevating extracellular GABA. Our data show how a transmembrane Ca(2+) source (TRPA1) targets a transporter (GAT-3) in astrocytes to regulate inhibitory synapses. 相似文献
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Mercer AJ Rabl K Riccardi GE Brecha NC Stella SL Thoreson WB 《Journal of neurophysiology》2011,105(1):321-335
Vesicle release from photoreceptor ribbon synapses is regulated by L-type Ca(2+) channels, which are in turn regulated by Cl(-) moving through calcium-activated chloride [Cl(Ca)] channels. We assessed the proximity of Ca(2+) channels to release sites and Cl(Ca) channels in synaptic terminals of salamander photoreceptors by comparing fast (BAPTA) and slow (EGTA) intracellular Ca(2+) buffers. BAPTA did not fully block synaptic release, indicating some release sites are <100 nm from Ca(2+) channels. Comparing Cl(Ca) currents with predicted Ca(2+) diffusion profiles suggested that Cl(Ca) and Ca(2+) channels average a few hundred nanometers apart, but the inability of BAPTA to block Cl(Ca) currents completely suggested some channels are much closer together. Diffuse immunolabeling of terminals with an antibody to the putative Cl(Ca) channel TMEM16A supports the idea that Cl(Ca) channels are dispersed throughout the presynaptic terminal, in contrast with clustering of Ca(2+) channels near ribbons. Cl(Ca) currents evoked by intracellular calcium ion concentration ([Ca(2+)](i)) elevation through flash photolysis of DM-nitrophen exhibited EC(50) values of 556 and 377 nM with Hill slopes of 1.8 and 2.4 in rods and cones, respectively. These relationships were used to estimate average submembrane [Ca(2+)](i) in photoreceptor terminals. Consistent with control of exocytosis by [Ca(2+)] nanodomains near Ca(2+) channels, average submembrane [Ca(2+)](i) remained below the vesicle release threshold (~ 400 nM) over much of the physiological voltage range for cones. Positioning Ca(2+) channels near release sites may improve fidelity in converting voltage changes to synaptic release. A diffuse distribution of Cl(Ca) channels may allow Ca(2+) influx at one site to influence relatively distant Ca(2+) channels. 相似文献
3.
Regulation of KCNQ channels by manipulation of phosphoinositides 总被引:2,自引:3,他引:2
Activation of phospholipase C (PLC) through G-protein-coupled receptors produces a large number of second messengers and regulates many physiological processes. Many membrane proteins including ion channels require the phosphoinositide phosphatidylinositol 4,5-bisphosphate (PIP2 ) to function. Activation of PLC can shut down their activity if it depletes the PIP2 pool strongly. Such a mechanism accounts for the muscarinic suppression of current in KCNQ channels. We describe a variety of methods used to show that these channels require PIP2 and that current in the channels is suppressed when receptor-activated PLC depletes PIP2 . The methods include observing translocation of lipid-sensitive protein domains, overexpression of enzymes of phosphoinositide metabolism, engineering these enzymes to move to the plasma membrane in response to a chemical signal, and direct chemical analysis of phospholipids. These approaches are general and can be used to test for PIP2 requirements of other membrane proteins. 相似文献
4.
Traditional models of synaptic transmission hold that release sites within an active zone operate independently. Although the release of multiple vesicles (multivesicular release; MVR) from single active zones occurs at some central synapses, MVR is not thought to require coordination among release sites. Ribbon synapses seem to be optimized to release many vesicles over an extended period, but the dynamics of MVR at ribbon synapses is unknown. We examined MVR at a ribbon synapse in a retinal slice preparation using paired recordings from presynaptic rod bipolar and postsynaptic AII amacrine cells. When evoked release was highly desynchronized, discrete postsynaptic events were larger than quantal miniature excitatory postsynaptic currents (mEPSCs) but had the same time course. The amplitude of these multiquantal mEPSCs, which seem to arise from the essentially simultaneous release of multiple vesicles, was reduced by lowering release probability. The release synchrony reflected in these multivesicular events suggests that release within an active zone is coordinated during MVR. 相似文献
5.
Tonic transmitter release in a graded potential synapse 总被引:2,自引:0,他引:2
Uusitalo R. O.; Juusola M.; Kouvalainen E.; Weckstrom M. 《Journal of neurophysiology》1995,74(1):470-473
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A Meir S Ginsburg A Butkevich S G Kachalsky I Kaiserman R Ahdut S Demirgoren R Rahamimoff 《Physiological reviews》1999,79(3):1019-1088
The primary function of the presynaptic nerve terminal is to release transmitter quanta and thus activate the postsynaptic target cell. In almost every step leading to the release of transmitter quanta, there is a substantial involvement of ion channels. In this review, the multitude of ion channels in the presynaptic terminal are surveyed. There are at least 12 different major categories of ion channels representing several tens of different ion channel types; the number of different ion channel molecules at presynaptic nerve terminals is many hundreds. We describe the different ion channel molecules at the surface membrane and inside the nerve terminal in the context of their possible role in the process of transmitter release. Frequently, a number of different ion channel molecules, with the same basic function, are present at the same nerve terminal. This is especially evident in the cases of calcium channels and potassium channels. This abundance of ion channels allows for a physiological and pharmacological fine tuning of the process of transmitter release and thus of synaptic transmission. 相似文献
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Effect of the KCNQ potassium channel opener retigabine on single KCNQ2/3 channels expressed in CHO cells 总被引:4,自引:3,他引:1
KCNQ2/3 potassium channel subunits were co-expressed in Chinese hamster ovary (CHO) cells and currents through single channels recorded using cell-attached patches. Channels had a similar slope conductance in the presence (8.04 ± 0.02 pS) and absence (7.6 ± 0.01 pS) of 10 μ m retigabine. The mean maximal open probability ( P o ) for single KCNQ2/3 channels was 0.13 ± 0.02, with a half-maximal P o potential ( V o ) of −28.7 ± 1.4 mV for control recordings. Retigabine increased mean maximal P o to 0.38 ± 0.04 and produced a hyperpolarising shift of V o to −40.1 ± 3.4 mV. Single KCNQ2/3 channels have multiple voltage-dependent kinetic components in their activity (CL -OS -CM -OL -CS ; C = closed, O = open, L = long, S = short, M = medium), giving short, medium and long closed times (τCS , τCM , τCL ) and short and long open times (τOS and τOL ). In the presence of retigabine at 0 mV the combined duration and contributions of the longest closed time τCL decreased tenfold, while the short and long open times increased fourfold and twofold, respectively. Thus, steady-state kinetics were modified to favour the open channel configuration. 相似文献
12.
Developmental changes in release properties of the CA3-CA1 glutamate synapse in rat hippocampus 总被引:3,自引:0,他引:3
Developmental changes in release probability (Pr) and paired-pulse plasticity at CA3-CA1 glutamate synapses in hippocampal slices of neonatal rats were examined using field excitatory postsynaptic potential (EPSP) recordings. Paired-pulse facilitation (PPF) at these synapses was, on average, absent in the first postnatal week but emerged and became successively larger during the second postnatal week. This developmental increase in PPF was associated with a reduction in Pr, as indicated by the slower progressive block of the N-methyl-D-aspartate (NMDA) EPSP by the noncompetitive NMDA receptor antagonist MK-801. This developmental reduction in Pr was not homogenous among the synapses. As shown by the MK-801 analysis, the Pr heterogeneity observed among adult CA3-CA1 synapses is present already during the first postnatal week, and the developmental Pr reduction was found to be largely selective for synapses with higher Pr values, leaving Pr of the vast majority of the synapses essentially unaffected. A reduction in Pves, the release probability of the individual vesicle, possibly caused by reduction in Ca2+ influx, seems to explain the reduction in Pr. In vivo injection of tetanus toxin at the end of the first postnatal week did not prevent the increase in PPF, indicating that this developmental change in release is not critically dependent on normal neural activity during the second postnatal week. 相似文献
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Hippocampal GABAergic interneurons show diverse molecular and morphological properties. The functional significance of this diversity for information processing is poorly understood. Here we show that cholecystokinin (CCK)-expressing interneurons in rat dentate gyrus release GABA in a highly asynchronous manner, in contrast to parvalbumin (PV) interneurons. With a gamma-frequency burst of ten action potentials, the ratio of asynchronous to synchronous release is 3:1 in CCK interneurons but is 1:5 in parvalbumin interneurons. N-type channels trigger synchronous and asynchronous release in CCK interneuron synapses, whereas P/Q-type Ca(2+) channels mediate release at PV interneuron synapses. Effects of Ca(2+) chelators suggest that both a long-lasting presynaptic Ca(2+) transient and a large distance between Ca(2+) source and sensor of exocytosis contribute to the higher ratio of asynchronous to synchronous release in CCK interneuron synapses. Asynchronous release occurs at physiological temperature and with behaviorally relevant stimulation patterns, thus generating long-lasting inhibition in the brain. 相似文献
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The coordination of T-cell migration and antigen recognition is crucial for an effective immune response. We have proposed that this coordination is achieved by formation of an immunological synapse between the T cell and the antigen-presenting cell (APC). Our view contrasts with the serial encounter model also proposed in this issue of Trends in Immunology, which is based on transient T cell-APC interactions when surrounded by collagen. Here, we propose a model that reconciles immunological synapse formation and serial encounters based on environmental control of immunological synapse formation. 相似文献
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A study of the mechanism of quantal transmitter release at a chemical synapse 总被引:13,自引:7,他引:13
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Zhanna L. Blioch Irina M. Glagoleva E. A. Liberman V. A. Nenashev 《The Journal of physiology》1968,199(1):11-35
1. The nerve-muscle preparation of the cutaneous pectoris of the frog has been used to study quantal transmitter release.2. When the osmotic pressure of the external solution is raised 1.5-2 fold, the frequency of miniature end-plate potentials (m.e.p.p.s) rises by 1.5-2 orders of magnitude. This effect is independent of the presence of Ca(2+) ions and of the nature of the substances by which the osmotic pressure has been increased.3. In Ca(2+) free hypertonic solution the nerve impulse still invades the nerve terminals but does not alter the frequency of the m.e.p.p.s.4. The arrival of the impulse in the terminals causes an immediate increase in the rate of quantal release, provided divalent cations are present whose passage through the axon membrane is facilitated by excitation (Ca(2+), Sr(2+), Ba(2+)).5. Divalent cations which penetrate only slightly (Mg(2+), Be(2+)) lower the frequency of m.e.p.p.s and suppress the end-plate potential (e.p.p.) evoked by an impulse, in the presence of Ca(2+) ions. Be(2+) is a more effective inhibitor than Mg(2+).6. In Ca(2+) free solutions, adding Mg(2+) causes an increase in the frequency of m.e.p.p.s evoked by depolarization of the nerve endings or by treatment with ethanol.7. The trivalent cation La(3+) is more effective than divalent cations are in increasing the frequency of m.e.p.p.s. The tetravalent cation Th(4+) also raises the m.e.p.p. frequency.8. The observations summarized in paragraphs 2-7 indicate that the frequency of m.e.p.p.s at a constant temperature depends only on the concentration of uni-, di- and trivalent cations inside the nerve ending. It is suggested that the internal cation concentration influences the adhesion between synaptic vesicles and the membrane of the nerve ending.9. For a model experiment, artificial phospholipid membranes have been used to study the effect of uni-, di-, tri- and tetravalent cations on the adhesion process. At pH 7-7.4, the time required for adhesion to take place decreases with increasing cation concentration in the bath. Ca(2+) ions are 100-1000 times more effective than K(+) ions; La(3+) and Th(4+) ions are still more effective. The ;adhesion time' decreases when the pH is lowered; it increases greatly with lowering of temperature.10. The hypothesis is put forward that the mutual adhesion of artificial vesicles made of phospholipid membranes, and the adhesion between synaptic vesicles and the membrane of the nerve ending arise by a common mechanism. In both cases, the important factor is the influence of cations on the electric double layer at the membrane surface. 相似文献
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Peroz D Rodriguez N Choveau F Baró I Mérot J Loussouarn G 《The Journal of physiology》2008,586(7):1785-1789
KCNQ1 is the pore-forming subunit of a channel complex whose expression and function have been rather well characterized in the heart. Almost 300 mutations of KCNQ1 have been identified in patients and a vast majority of the described mutations are linked to the long QT syndrome. Only a few mutations are linked to other pathologies such as atrial fibrillation and the short QT syndrome. However, a considerable amount of work remains to be done to get a clear picture of the molecular mechanisms responsible for the pathogenesis related to each mutation. The present review gives three examples of recent studies towards this goal and illustrates the diversity of the molecular mechanisms involved. 相似文献
18.
Sergey Missan Jiansong Qi Julie Crack Terence F. McDonald Paul Linsdell 《Pflügers Archiv : European journal of physiology》2009,458(3):471-480
The objective of the study was to investigate the role of tyrosine phosphorylation in the regulation of KCNQ1/KCNE1 channels.
Large whole-cell time- and voltage-dependent K+ currents were present in human embryonic kidney 293 cells cotransfected with human KCNQ1 and KCNE1 but not in control nontransfected
cells. The time- and voltage-dependent current had biophysical properties typical of cardiac KCNQ1/KCNE1 current and was almost
completely abolished by KCNQ1 blocker chromanol 293B (50 μM). Both KCNQ1/KCNE1 and KCNQ1 current were inhibited in a voltage-independent
manner by tyrosine kinase (PTK) inhibitor tyrphostin A25 (100 μM), but not by PTK-inactive tyrphostin A1 (100 μM), suggesting
involvement of tyrosine phosphorylation in maintaining channel activity. This view was strengthened by the finding that phosphotyrosyl
phosphatase inhibitor monoperoxo(picolinato)-oxo-vanadate(V) (200 μM) reversed the inhibition of current by tyrphostin A25.
However, the channel-pertinent tyrosine phosphorylation modulated by these compounds does not appear to be on the channel
itself because inhibition of current by tyrphostin A25 was unaffected by single and multiple mutations of KCNQ1 cytoplasmically
accessible tyrosine residues. Inhibition by tyrphostin A25 was unaffected by intracellularly applied diC8 phosphatidylinositol-4,5-bisphosphate
(diC8 PIP2; 25 μM), and based on the results obtained from cell surface biotinylation experiments, it was not due to loss of channels
from the membrane. We conclude that tyrphostin A25 inhibits KCNQ1/KCNE1 current by lowering tyrosine phosphorylation on unidentified
nonchannel protein(s) that directly or indirectly regulate the open probability of the KCNQ1 pore in a PIP2-independent manner. 相似文献
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Zefirov AL Khaliullina RR Sokolova EM Giniatullin RA 《Neuroscience and behavioral physiology》2000,30(5):569-574
Experiments on neuromuscular preparations of frog skin-thoracic muscle and sartorius muscle, using extracellular recording
and two-electrode clamping of the muscle fiber membrane potential, were used to study the effects of the nitric oxide donor
sodium nitroprusside on endplate currents. At a concentration of 100 μM, sodium nitroprusside sharply decreased the amplitude
and quantum composition of the endplate currents, and also decreased the miniature endplate current frequency. The amplitude-time
characteristics of miniature endplate currents, the voltage-dependent amplitude, and the decay time constant of miniature
endplate currents did not change as compared with controls. However, unlike the situation with other secretion inhibitors,
the decrease in endplate current amplitude was not accompanied by increased facilitation in response to rhythmic stimulation
or changes in postsynaptic potentiation in conditions of application of pairs of stimuli to muscles. The suppression of acetylcholine
secretion was not seen with inactivated sodium nitroprusside solution. These results provide evidence that nitric oxide can
be a powerful inhibitor of both spontaneous and evoked transmitter secretion in the neuromuscular synapse, and that this is
accompanied by decreases in the efficiency of presynaptic forms of short-term plasticity, while the functional characteristics
of the postsynaptic membrane remain unchanged.
Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 85, No. 5, pp. 663–670, May, 1999. 相似文献
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Experience-dependent modification in the electrical properties of central neurons is a form of intrinsic plasticity that occurs during development and has been observed following behavioral learning. We report a novel form of intrinsic plasticity in hippocampal CA1 pyramidal neurons mediated by the KV7/KCNQ and CaV1/L-type Ca2+ channels. Enhancing Ca2+ influx with a conditioning spike train (30 Hz, 3 s) potentiated the KV7/KCNQ channel function and led to a long-lasting, activity-dependent increase in spike frequency adaptation—a gradual reduction in the firing frequency in response to sustained excitation. These effects were abolished by specific blockers for CaV1/L-type Ca2+ channels, KV7/KCNQ channels, and protein kinase A (PKA). Considering the widespread expression of these two channel types, the influence of Ca2+ influx and subsequent activation of PKA on KV7/KCNQ channels may represent a generalized principle in fine tuning the output of central neurons that promotes stability in firing—an example of homeostatic regulation of intrinsic membrane excitability. 相似文献