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1.
The membrane of the endoplasmic reticulum is, in fact, an extension of the nuclear envelope of eukaryotic cells; both these
compartments can fulfill the function of intracellular calcium stores. Using a patch-clamp technique, we studied the biophysical
properties of the channels expressed in the inner nuclear membrane of pyramidal neurons of the rat hippocampal CA1 area, in particular of large-conductance cationic channels and calcium channels of inositol trisphosphate receptors (the
main channels in membranes of this type). As the results of the measurements showed, the activity of channels of both types
demonstrates clearly pronounced voltage dependences. The probability of their open state (P
o) depends on the voltage inside the nuclear envelope lumen. At positive potentials, the activity of these channels is significantly
more intense than at negative potentials. Moreover, channels of both types are reversibly blocked at considerable negative
potentials. We believe that this property of ion channels in the nuclear envelope is an important factor responsible for the
control of calcium signals in the cell nucleus. We propose a hypothesis on the mechanism underlying termination of Ca2+ release from such intracellular stores, which is based on the specificity of the voltage dependence of ion channels of the
above-mentioned types. 相似文献
2.
As is known, an increase in the concentration of Са2+ in the nuclei of nerve cells leads to activation of genes responsible for the formation of long-lasting postsynaptic changes;
mechanisms of memory and learning are based on such changes. The pathways necessary for the entry of calcium into the nuclei
of hippocampal pyramidal neurons remained unstudied. Using a patch-clamp technique, we studied what types of calcium channels
exist in the membranes of isolated nuclei of pyramidal neurons of the hippocampal СА1 area. In the inner nuclear membrane of these cells, we, for the first time, found inositol trisphosphate receptors (IP3Rs) activated by inositol trisphosphate applied in the concentration of ≥0.1 μM. The conductivity of single channels of such
receptors was, on average, 366 pS; these channels were permeable for both monovalent and bivalent cations. Our data indicate
that the nuclear envelope of pyramidal neurons of the hippocampal СА1 area can play the role of the calcium store from which Са2+ enter the cell nucleus directly.
Neirofiziologiya/Neurophysiology, Vol. 40, No. 4, pp. 288–292, July–August, 2008. 相似文献
3.
The genetic apparatus of an eukaryotic cell is surrounded by two membranes of the nuclear envelope that forms a half-permeable
barrier for the movement of molecules and ions. Using a patch-clamp technique in experiments on isolated nuclei of pyramidal
neurons from the hippocampal CA1 area, we describe the biophysical properties of spontaneously active ion channels in the nuclear membranes of these cells.
In the external nuclear membrane, we found anion channels with a unitary conductance of 156 pS and with very rapid kinetics
of fluctuation, while in the inner membrane we recorded cationic channels with a unitary conductance of 248 pS and very slow
kinetics. Channels of both types demonstrated clear voltage dependences. We hypothesize that the physiological importance
of these channels is related to the function of the intermembrane space of the nuclear envelope of these cells forming a considerable
calcium store. It seems possible that such channels in the nuclear membranes are necessary for the maintenance of the ion
balance between the cytoplasm and perinuclear space and between the latter and karyoplasm, and also for neutralization of
voltage shifts in the course of Ca2+ release.
Neirofiziologiya/Neurophysiology, Vol. 39, No. 1, pp. 3–8, January–February, 2007. 相似文献
4.
The responses of freshly isolated hippocampal pyramidal neurons to rapid, elevations of the external potassium concentration
([K+]
out
) were investigated using the whole-cell variation of a patch-clamp technique. An elevation of [K+]
out
induced a two-phase inward current at the membrane potentials more negative than the reversal potential for K ions. This
current consisted of a leakage, current and a time-dependent current (τ=40–50 msec at 21°C), the latter designated below asI
ΔK. It displayed first-order activation kinetics that showed neither voltage, nor concentration dependence. The amplitude of
this current was determined by the external K+ concentration and increased with hyperpolarization. Voltage dependence ofI
ΔK measured within the range from −20 to −120 mV was similar to that for inward rectifier. Activation ofI
ΔK was utterly dependent on Na+; substitution of extracellular Na+ with choline chloride almost completely depressedI
ΔK.I
ΔK was absent in the cells freshly dissociated from the nodosal and dorsal root ganglia. This suggests that this earlier unrecognized
current is instrumental in preserving densely packed hippocampal pyramidal neurons from sudden increases in [K+]
out
and following spontaneous over-excitation. It prevents the neurons from responding to K+-induced depolarizations by slowing down potassium influx. 相似文献
5.
Using a microelectrode technique, we studied the effects of alimentary vitamin В1 deficiency on synaptic transmission in isolated phrenico-hemidiaphragmatic murine preparations. Animals of group І (control)
were on a standard thiamine-controlled diet (16 mg/kg thiamine) with no limitations. Animals of group II (control with alimentary
limitation) were on the same diet, but daily consumption in these animals was limited and made similar to the amount of food
consumed by the animals of group ІІІ within idential periods of cage housing (for differentiation of the effects of anorexia
related to the thiamine-deficient state in group III and proper effects of В1 hypovitaminosis). Animals of group ІІІ (thiamine-deficient) were on a standard diet (with no limitations) mostly analogous
to that in group І but containing no thiamine. In phrenicohemidiaphragmatic preparations obtained from animals of group ІІІ,
the amplitude of end-plate potentials (EPPs) and miniature EPPs (mEPPs) on the 10th day of consumption of the thiamine-defficient
diet and the quantum composition of EPPs on the 20th day became significantly (Р < 0.01) smaller than in preparations obtained from animals of both groups І and ІІ. The frequency of mEPPs and membrane potential
of muscle fibers in group ІІІ remained unchanged. Two processes, a decrease in the dimension of the transmitter quantum (which
is observed within rather early stages of the development of thiamine-defficient state) and a decrease in the quantum composition
of evoked EPPs (at later stages) underlie a gradual decrease in the amplitude of EPPs related to the development of alimentary
vitamin В1 deficiency.
Neirofiziologiya/Neurophysiology, Vol. 40, No. 4, pp. 322–331, July–August, 2008. 相似文献
6.
Dose-dependent neurotoxic effects (decrease in the amplitude of field potentials generated by neurons of the СА1 area, dentate gyrus, and dorsal striatum, but not by neurons of layers ІІ and ІІІ of the parietal cortex, recorded in slices
of the rat brain) were observed 24 h after i.p. injection оf dexamethasone in doses of 7 and 20 mg/kg. Dexamethasone-induced
decreases in the reactivity of glutamatergic synapses in the studied cerebral structures were weakened by a noncompetitive
blocker of NMDA receptors, ketamine (30 mg/kg), and an inhibitor of tyrosine protein phosphatases, sodium vanadate (15 mg/kg),
if the latter agent was injected 6 h after dexamethasone administration. The neurotoxic effect of dexamethasone was intensified
by a coagonist of NMDA receptors, glycine (50 mg/kg), as well as in the case where injections of dexamethasone were combined
with single injections of the antidepressant fluoxetine (20 mg/kg) but not when another antidepressant, pyrazidol, was injected
in the same dose. Chronic (two weeks) injections of fluoxetine and pyrazidol weakened manifestations of dexamethasone neurotoxicity.
On-regulation of NMDA receptors and suppression of expression of neurotrophins are considered probable mechanisms underlying
neurotoxicity of this hormone. The effect of chronic injections of antidepressants on the respective processes is discussed.
Neirofiziologiya/Neurophysiology, Vol. 40, No. 4, pp. 312–231, July–August, 2008. 相似文献
7.
V. P. Tsintsadze A. L. Fedorenko T. Sh. Tsintsadze M. Wright J. A. Tanner A. D. Miller N. A. Lozovaya 《Neurophysiology》2006,38(3):169-174
Using a patch-clamp technique under voltage clamp conditions, we studied the effect of a non-hydrolyzable analog of diadenosine
polyphosphates (AppCH2ppAs) on chemoactivated transmembrane currents through NMDA channels (NMDA currents) in isolated pyramidal neurons of the
rat hippocampal CA3 zone. In 55.7% of the cases, AppCH2ppAs caused an increase in the peak amplitude of the currents induced by application of aspartate. In 39.5% of the cases,
the agent exerted no effect, while in 4.8% these currents were suppressed. When studying the pharmacological effect of an
increase in the amplitude of NMDA currents, we found that potentiation of these currents is mediated, first of all, by activation
of P2 purinoceptors and is prevented by a blocker of tyrosine kinases, genistein. Receptor-channel NMDA complexes, due to their
ability to be blocked by divalent cations, also contribute to the above effect of AppCH2ppA. Based on the data obtained, we conclude that AppCH2ppA influences NMDA receptors via activation of the P2 receptors and subsequent activation of tyrosine kinases; this leads to the modification of receptor-channel NMDA complexes
and to the removal of their tonic blocking by zinc ions.
Neirofiziologiya/Neurophysiology, Vol. 38, No. 3, pp. 205–210, May–June, 2006. 相似文献
8.
The dependence of currents through the cyclic nucleotide-gated (CNG) channels of mammalian olfactory receptor neurons (ORNs)
on the concentration of NaCl was studied in excised inside-out patches from their dendritic knobs using the patch-clamp technique.
With a saturating concentration (100 μm) of adenosine 3′, 5′-cyclic monophosphate (cAMP), the changes in the reversal potential of macroscopic currents were studied
at NaCl concentrations from 25 to 300 mm. In symmetrical NaCl solutions without the addition of divalent cations, the current-voltage relations were almost linear,
reversing close to 0 mV. When the external NaCl concentration was maintained at 150 mm and the internal concentrations were varied, the reversal potentials of the cAMP-activated currents closely followed the
Na+ equilibrium potential indicating that P
Cl/P
Na≈ 0. However, at low external NaCl concentrations (≤100 mm) there was some significant chloride permeability. Our results further indicated that Na+ currents through these channels: (i) did not obey the independence principle; (ii) showed saturation kinetics with K
ms in the range of 100–150 mm and (iii) displayed a lack of voltage dependence of conductance in asymmetric solutions that suggested that ion-binding sites
were situated midway along the channel. Together, these characteristics indicate that the permeation properties of the olfactory
CNG channels are significantly different from those of photoreceptor CNG channels.
Received: 7 November 1996/Revised: 24 March 1997 相似文献
9.
V. A. Bouryi 《Neurophysiology》1999,31(6):361-364
We investigated the voltage dependence of nifedipine sensitivity of the ion channels formed by α1 subunits of the cardiac and smooth muscles (CM and SM, respectively) L-type Ca2+ channels stably expressed in Chinese hamster ovary (CHO) cells. Equilibrium inhibition of the α1 subunits, directing Ba2+ current (I
α1), by different concentrations of nifedipine was measured at the holding potentials (V
h
) of −100 mV and −50 mV. AtV
h
=−100 mV, the SM α1 subunit was found to be 6-fold more sensitive for nifedipine than the subunit (K
−100=8.3 and 50.4 nM, respectively). Depolarization to −50 mV resulted in about sevenfold increase in the nifedipine potency for
both subunits (K
−50=1.25 and 6.95 nM, respectively). The voltage dependence of steady-state inactivation could be fitted by a sum of two Boltzmann’s
equations with slope factors of about 12 and 5 mV. The midpoints of both components in the CM α1 subunit (−75.6 and −42.8 mV) were more negative than those in the SM subunit (−63.7 and −37.7 mV). The relative contribution
of the less sloped component in the control was rather low, being less pronounced in the CM (0.15) than in the SM (0.34) subunits.
Nifedipine shifted the midpoints of inactivation curves to more negative potentials. The shift was more pronounced for the
SM α1 subunit (−24.8 mV compared with −11.8 mV for the CM subunit in the presence of 10 nM nifedipine). Nifedipine differentially
affected the two Boltzmann components of inactivation curves, more effectively inhibiting the steeper component. In the presence
of 10 nM nifedipine, this component completely disappeared in the SM subunit, while its relative contribution in the CM subunit
decreased from 0.85 to 0. 57, resulting in an apparent decrease in the steepness. These results are inconsistent with the
receptor modulated hypothesis and suggest the existence of two mechanisms of inactivation characterized by different voltage
dependence. 相似文献
10.
N. N. Razoumnaya 《Neurophysiology》2011,43(3):233-235
In experiments on rat brain slices using extracellular recording, we studied the effects of an agonist of β2 adrenoreceptors, metaproterenol (MPT), on reactions of pyramidal neurons of the hippocampal CA1 area induced by activation of GABAB receptors. Isolated application of an agonist of GABAB receptors, baclofen (10 μM), resulted in intense inhibition (by 50% or more during the 1st min of action) of orthodromic
field discharges (OFDs) in the pyramidal layer of the above-mentioned area of the hippocampus; the discharges were evoked
by electrical stimulation of Schaffer collaterals. On the 3rd to 4th min, OFDs were suppressed nearly completely. After washing
out from baclofen, the parameters of the evoked responses never completely restored to the initial level. In all cases, simultaneous
application of 150 μM MPT and 10 μM baclofen prevented full manifestation of the inhibitory effect of the latter agent on
OFDs of pyramidal neurons. The amplitude of evoked responses decreased, but the relative intensity of inhibition under these
conditions during 2-min-long application was significantly lower than that upon isolated action of baclofen. The recovery
of the amplitude of evoked responses in the course of washing out under conditions of parallel action of MPT was more rapid
and, in some cases, complete. Therefore, our experiments showed that GABAB-ergic inhibitory transmission in the rat hippocampal CA1 area in vitro can be suppressed significantly by the β2 adrenoreceptor agonist. 相似文献
11.
Recently, we proposed a quantitative model to explain the molecular mechanism of action of the Tityus serrulatus Ts3 α-toxin on sodium channels. In this model, the toxin acts as a stop that prevents the segment S4 of domain IV from reaching
its outermost position, thus impairing the normal fast inactivation without affecting activation. In the present work, we
analyze the predictions of the proposed model with regard to the voltage-dependent transitions to and from inactivation. Our
results show that the recovery from inactivation was significantly faster in Ts3-bound channels and that there was no significant
voltage dependence. The transition to inactivated state from open state in Ts3-modified channels presented a small but significant
voltage dependence, which may derive from an intrinsic voltage dependence of inactivation or by a short movement of IVS4 in
the presence of bound Ts3. We also studied the thermodynamic parameters of the voltage-dependent displacement of Ts3 from
its binding site. We have observed that the activation energy to remove the toxin is 27 kJ/mol, part of which derives from
the imposed depolarizing potential and the movement of an equivalent electrical charge of 0.54 c
0. These results support the proposed model. 相似文献
12.
A detailed temperature dependence study of a well-defined plant ion channel, the Ca2+-activated K+ channel of Chara corallina, was performed over the temperature range of their habitats, 5–36°C, at 1°C resolution. The temperature dependence of the
channel unitary conductance at 50 mV shows discontinuities at 15 and 30°C. These temperatures limit the range within which
ion diffusion is characterized by the lowest activation energy (E
a
= 8.0 ± 1.6 kJ/mol) as compared to the regions below 15°C and above 30°C. Upon reversing membrane voltage polarity from 50
to −50 mV the pattern of temperature dependence switched from discontinuous to linear with E
a
= 13.6 ± 0.5 kJ/mol. The temperature dependence of the effective number of open channels at 50 mV showed a decrease with increasing
temperature, with a local minimum at 28°C. The mean open time exhibited a similar behavior. Changing the sign of membrane
potential from 50 to −50 mV abolished the minima in both temperature dependencies. These data are discussed in the light of
higher order phase transitions of the Characean membrane lipids and corresponding change in the lipid-protein interaction,
and their modulation by transmembrane voltage.
Received: 14 June 2000/Revised: 20 September 2000 相似文献
13.
K. H. Kim V. E. Gmiro D. B. Tikhonov L. G. Magazanik 《Biochemistry (Moscow) Supplemental Series A: Membrane and Cell Biology》2007,1(1):88-95
9-Aminoacridine and tacrine differ from other channel blockers of NMDA receptors in that their binding prevents the closing
of blocked channels and subsequent dissociation of the agonist. Structural determinants of aminoacridine derivatives underlying
the blocking mechanism are still unknown. The aim of this study was to elucidate the effects of a dicationic 9-aminoacridine
derivative and some other tricyclic compounds on NMDA receptors of rat hippocampal pyramidal neurons. All the compounds under
study are voltage-dependent blockers of NMDA channels; their IC50 values recorded at −80 mV vary from 1 to 50 μM. The dicationic derivatives demonstrate the same voltage dependence of the
block as the monocationic derivatives. The monoand dicationic tricyclic compounds under study are weak blockers of AMPA receptor
channels and differ from adamantane, phenylcyclohexyl and other dicationic derivatives that exhibit greater voltage dependence
of the NMDA channel block and are able to induce effective suppression of AMPA channels. We conclude that the mechanisms of
action of the tricyclic and dicationic 9-aminoacridine derivatives are different from that of 9-aminoacridine, since these
compounds do not prevent closing of the blocked channels. This suggests that the binding site for 9-aminoacridine has specific
properties and high selectivity with respect to ligand structure.
Original Russian Text ? K.H. Kim, V.E. Gmiro, D.B. Tikhonov, L.G. Magazanik, 2007, published in Biologicheskie Membrany, 2007,
Vol. 24, No. 1, pp. 96–104. 相似文献
14.
Yu. V. Kirichok Ya. A. Boychuk M. V. Kopanitsa T. Sh. Tsintsadze N. A. Lozovaya O. A. Krishtal 《Neurophysiology》2000,32(1):12-16
The effects of a novel anti-hypertensive drug, mibefradil, on voltage-dependent currents in isolated thalamic and hippocampal
neurons, as well as on synaptic transmission in the hippocampus have been studied. Mibefradil exerted a potent inhibitory
action on low-threshold calcium currents in thalamic neurons (IC50=160 nM). In higher concentrations (1–20 μM), this drug blocked not only low-threshold calcium current but also voltage-dependent
sodium and delayed potassium currents in pyramidal hippocampal neurons. The amplitude of population action potentials in hippocampal
slices decreased by 55% in the presence of 20μM mibefradil. All of the effects of mibefradil were almost completely reversible.
In our experiments, the sensitivity of low-threshold calcium channels in thalamic neurons to mibefradil was higher than that
observed on other objects. The ability of mibefradil to block not only calcium currents but also other types of voltage-dependent
ion conductances in hippocampal neurons may be considered an essential factor that determines the specificity of the pharmacological
profile of this drug. 相似文献
15.
Augustus O. Grant David J. Wendt Yuri Zilberter C. Frank Starmer 《The Journal of membrane biology》1993,136(2):199-214
Block of cardiac sodium channels is enhanced by repetitive depolarization. It is not clear whether the changes in drug binding
result from a change in affinity that is dependent on voltage or on the actual state of the channel. This question was examined
in rabbit ventricular myocytes by analyzing the kinetics of block of single sodium channel currents with normal gating kinetics
or channels with inactivation and deactivation slowed by pyrethrin toxins. At −20 and −40 mV, disopyramide 100 μm blocked the unmodified channel. Mean open time decreased45 and34% at −20 and −40 mV during exposure to disopyramide. Exposure of cells to the pyrethrin toxins deltamethrin or fenvalrate caused at least a tenfold
increase in mean open time, and prominent tail currents could be recorded at the normal resting potential. The association
rate constant of disopyramide for the normal and modified channel at −20 mV was similar, ∼10×106/m/sec. During exposure to disopyramide, changes in open and closed times and in open channel noise at −80 and −100 mV are consistent
with fast block and unblocking events at these potentials. This contrasts with the slow unbinding of drug from resting channels
at similar potentials. We conclude that the sodium channel state is a critical determinant of drug binding and unbinding kinetics. 相似文献
16.
Victoria A. L. Seymour Andrea B. Everitt M. Louise Tierney 《The Journal of membrane biology》2009,227(3):111-122
Hippocampal pyramidal neurons potentially express multiple subtypes of GABAA receptors at extrasynaptic locations that could therefore respond to different drugs. We activated extrasynaptic GABAA receptors in cultured rat hippocampal pyramidal neurons and measured single-channel currents in order to compare the actions
of two drugs that potentially target different GABAA receptor subtypes. Despite the possible difference in receptor targets of etomidate and diazepam, the two drugs were similar
in their actions on native extrasynaptic GABAA receptors. Each drug produced three distinct responses that differed significantly in current magnitude, implying heterogeneous
GABAA receptor populations. In the majority of patches, drug application increased both the single-channel conductance (>40 pS)
and the open probability of the channels. By contrast, in the minority of patches, drug application caused an increase in
open probability only. In the third group high-conductance channels were observed upon GABA activation and drug application
increased their open probability only. The currents potentiated by etomidate or diazepam were substantially larger in patches
displaying high-conductance GABA channels compared to those displaying only low-conductance channels. Factors contributing
to the large magnitude of these currents were the long mean open time of high-conductance channels and the presence of multiple
channels in these patches. In conclusion, we suggest that the local density of extrasynaptic GABAA receptors may influence their single-channel properties and may be an additional regulating factor for tonic inhibition and,
importantly, differential drug modulation.
This work is dedicated to the memory of Professor P. W. Gage. 相似文献
17.
A number of peptide toxins derived from marine snails and various spiders have been shown to potently inhibit voltage-dependent
calcium channels. Here, we describe the effect of calcicludine, a 60 amino-acid peptide isolated from the venom of the green
mamba (Dendroaspis angusticeps), on transiently expressed high voltage-activated calcium channels. Upon application of calcicludine, L-type (α1
C
) calcium channels underwent a rapid, irreversible decrease in peak current amplitude with no change in current kinetics,
or any apparent voltage-dependence. However, even at saturating toxin concentrations, block was always incomplete with a maximum
inhibition of 58%, indicating either partial pore block, or an effect on channel gating. Block nonetheless was of high affinity
with an IC50 value of 88 nm. Three other types of high voltage activated channels tested (α1
A
, α1
B
, and α1
E
) exhibited a diametrically different response to calcicludine. First, the maximal inhibition observed was around 10%, furthermore,
the voltage-dependence of channel activation was shifted slightly towards more negative potentials. Thus, at relatively hyperpolarized
test potentials, calcicludine actually upregulated current activity of (N-type) α1
B
channels by as much as 50%. Finally, the use of several chimeric channels combining the major transmembrane domains of α1
C
and α1
E
revealed that calcicludine block of L-type calcium channels involves interactions with multiple structural domains. Overall,
calcicludine is a potent and selective inhibitor of neuronal L-type channels with a unique mode of action.
Received: 22 September 1999/Revised: 1 December 1999 相似文献
18.
I. V. Melnick 《Neurophysiology》2011,42(4):239-243
Upon application of a long-lasting rectangular stimulus, neurons of the substantia gelatinosa (SG) display three main types of intrinsic firing behavior, tonic, adapting, and delayed onset. The electrical landmark of delayed-firing
neurons (DFNs), i.e., a significant delay before initiation of action potentials (APs), is believed to result from activation
of subthreshold A-type K+ current (KA). We checked out this hypothesis by comparing the voltage dependence of the firing delay with steady-state inactivation of
KA in spinal cord slices of 3- to 5-week-old rats. The delay strongly decreased with membrane depolarization and disappeared
at ~ –60 mV; herewith the discharge pattern was transformed to either a tonic or an adapting one. This correlated well with
inactivation of KA recorded in a whole-cell mode in low-Cl– intracellular solution; inactivation was nearly complete at –60 mV (voltage of half-maximum inactivation, V
1/2 ~ –74.5 mV). Unexpectedly, it was found that filling the cells with high-Cl– solution, to minimize the liquid junction potential, produced at least a 10 mV-difference between voltage dependences of
the firing delay and KA inactivation; the latter shifted toward negativity (V
1/2 ~ –88.3 mV). The results suggest that the KA and its inactivation properties determine the appearance and voltage dependence of the firing delay in SG neurons; the apparent influence of intracellular Cl– on inactivation properties needs further investigation. 相似文献
19.
Nicotinic acetylcholine receptors are heteropentameric ion channels that open upon activation to a single conducting state. The second transmembrane segments of each subunit were identified as channel-forming elements, but their respective contribution in the gating process remains unclear. Moreover, the detailed impact of variations of the membrane potential, such as occurring during an action potential, on the transmembrane domains, is unknown. Residues at the 12′ position, close to the center of each second transmembrane segment, play a key role in channel gating. We examined their functional symmetry by substituting a lysine to that position of each subunit and measuring the electrical activity of single channels. For 12′ lysines in the α, γ and δ subunits rapid transitions between an intermediate and large conductance appeared, which are interpreted as single lysine protonation events. From the kinetics of these transitions we calculated the pK
a values of respective lysines and showed that they vary differently with membrane hyperpolarization. Respective mutations in β or ε subunits gave receptors with openings of either intermediate or large conductance, suggesting extreme pK
a values in two open state conformations. The results demonstrate that these parts of the highly homologous transmembrane domains, as probed by the 12′ lysines, sense unequal microenvironments and are differently affected by physiologically relevant voltage changes. Moreover, observation of various gating events for mutants of α subunits suggests that the open channel pore exists in multiple conformations, which in turn supports the notion of functional asymmetry of the channel. 相似文献
20.
The aim of the present paper was to examine, in a comparative way, the occurrence and the mechanisms of the interactions between adenosine A2A receptors (A2ARs) and metabotropic glutamate 5 receptors (mGlu5Rs) in the hippocampus and the striatum. In rat hippocampal and corticostriatal slices, combined ineffective doses of the mGlu5R agonist 2-chloro-5-hydroxyphenylglycine (CHPG) and the A2AR agonist CGS 21680 synergistically reduced the slope of excitatory postsynaptic field potentials (fEPSPs) recorded in CA1 and the amplitude of field potentials (FPs) recorded in the dorsomedial striatum. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway appeared to be involved in the effects of CGS 21680 in corticostriatal but not in hippocampal slices. In both areas, a postsynaptic locus of interaction appeared more likely. N-methyl-D-aspartate (NMDA) reduced the fEPSP slope and FP amplitude in hippocampal and corticostriatal slices, respectively. Such an effect was significantly potentiated by CHPG in both areas. Interestingly, the A2AR antagonist ZM 241385 significantly reduced the NMDA-potentiating effect of CHPG. In primary cultures of rat hippocampal and striatal neurons (ED 17, DIV 14), CHPG significantly potentiated NMDA-induced lactate dehydrogenase (LDH) release. Again, such an effect was prevented by ZM 241385. Our results show that A2A and mGlu5 receptors functionally interact both in the hippocampus and in the striatum, even though different mechanisms seem to be involved in the two areas. The ability of A2ARs to control mGlu5R-dependent effects may thus be a general feature of A2ARs in different brain regions (irrespective of their density) and may represent an additional target for the development of therapeutic strategies against neurological disorders. 相似文献