GABA
            <sub>A</sub>
            -Receptor Function in Hippocampal Cells Is Maintained by Phosphorylation Factors

Stelzer, Armin; Kay, Alan R.; Wong, Robert K. S.

doi:10.1126/science.2455347

Cited by 291 publications

(141 citation statements)

References 34 publications

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“…The results demonstrated that the rate of run-down was dependent on the concentration of GABA used to activate the cell reponse. In contrast, our studies show that run-down of the GABAA response in the hippocampus is independent of the concentration of agonist applied since the run-down still occurred without GABA application (Stelzer & Wong, 1987;Stelzer et al 1988). The differences in the result could be due to variations in experimental conditions or the GABAA receptor structure in the two types of neurones.…”

Section: Discussioncontrasting

confidence: 40%

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GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea‐pig hippocampal neurones.

Chen

Stelzer

Kay

et al. 1990

The Journal of Physiology

291

166

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SUMMARY1. Current mediated by GABAA receptors was examined in pyramidal cells acutely dissociated from the hippocampus of mature guinea-pigs. Current responses were measured using whole-cell voltage-clamp recordings. An internal perfusion technique was used to change the intracellular contents during recording.2. Application of GABA (100-300 /M) by short duration pressure pulses produced outward current responses at a holding potential of -10 mV. When recordings were made with intracellular solutions which did not contain Mg-ATP, GABA responses progressively decreased to less than 10% of their initial values after 10 min. This 'run-down' of the GABA response could not be accounted for by desensitization since the rate of run-down was not dependent upon agonist application.3. The run-down of the GABAA response was reversed when Mg2+ (4 mM) and ATP (2 mM) were introduced into the intracellular perfusate. In addition to the presence of Mg-

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Section: Discussioncontrasting

confidence: 40%

“…as the reversal potential of the (GABA-activated current remained constant throughout the time course of recording (Stelzer et al 1988).…”

Section: Resultsmentioning

confidence: 99%

GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea‐pig hippocampal neurones.

Chen

Stelzer

Kay

et al. 1990

The Journal of Physiology

291

166

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“…To determine possible mIPSC rundown 18 , we followed cells over the same time course as in the Ca 2+ -free experiments without changing the external solution ('sham experiments'). No significant change occurred in the mIPSC amplitude ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

et al. 2000

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articlesThe building block of synaptic transmission is the quantum, the minimal increment of postsynaptic signals 1 . At vertebrate neuromuscular junctions, the quantum may be equated with spontaneous signals obtained in the absence of presynaptic action potentials, called miniature currents (or potentials) and believed to be due to release of one neurotransmitter vesicle. For central synapses, this issue remains an open question, as large miniature currents are suggested to arise from the concerted release of several presynaptic vesicles and to be the sum of several quanta 2-5 . Such multivesicular miniature events could reflect tetrodotoxinresistant action potentials in presynaptic terminals 6 . Another explanation comes from evidence for functional intracellular Ca 2+ stores in presynaptic terminals. First, inositoltrisphosphate (InsP 3 ) receptors are immunolocalized in presynaptic terminals of the deep cerebellar nuclei and retina 7,8 . Second, at the frog neuromuscular junction, agents that affect ryanodine-sensitive Ca 2+ stores also regulate presynaptic intracellular Ca 2+ (Ca 2+ i ) rises and acetylcholine release during high-frequency stimulation 9,10 . Third, action-potential-evoked release of acetylcholine at synapses in Aplysia buccal ganglia is inhibited by ryanodine and augmented by presynaptic injection of cyclic ADP ribose 11 . Fourth, caffeine and/or ryanodine modify presynaptic Ca 2+ i signals in autonomic ganglia 12,13 and in photoreceptors 14 . Finally, in hippocampal pyramidal cells, caffeine or thapsigargin can increase the frequency of miniature IPSCs 15 . Hence, spontaneous Ca 2+ release from presynaptic Ca 2+ stores may provide the synchronization mechanism that leads to multivesicular miniatures. However, except for one study that gave negative results in cultured retinal amacrine cells 16 , this possibility has not been tested systematically.To assess the contribution of intracellular Ca 2+ stores to neurotransmitter release, we monitored the amplitude distribution of miniature synaptic currents while manipulating potential presynaptic Ca 2+ stores. Using cerebellar interneuron-Purkinje cell synapses, in which large miniature synaptic currents are prominent, we found that the largest mIPSCs result from multivesicular release and depend on Ca 2+ mobilization from ryanodine-sensitive presynaptic stores. Further, two-photon confocal microscopy showed ryanodine-sensitive intracellular Ca 2+ i transients highly localized to presumed release sites, which may underlie large miniature currents. RESULTSMiniature IPSCs recorded in cerebellar Purkinje cells, at -60 mV under symmetrical Cl -concentrations and in the presence of tetrodotoxin (TTX) and ionotropic glutamate receptor blockers, showed mean amplitudes of 125 ± 9 pA (n = 28 cells), larger than for most neurons (Fig. 1a). Amplitude histograms had a distinct peak for values less than 200 pA, followed by a long tail with amplitudes up to 1500 pA (Fig. 1b). Spurious summation of independent events did not contribute to the generation of lar...

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“…Experiments investigating the pharmacology of the GABA response in spinal neurones were postponed for 10-20min, sufficient time for GABA-activated currents to become consistent in amplitude. The phenomenon of GABA-evoked current rundown was not quantified in this study but has previously been documented and is believed to be caused by the loss of ATP from the intracellular milieu due to dialysis by the recording electrode (Stelzer et al, 1988;Song & Huang, 1990). In contrast to currents activated by GABA, those evoked by glycine did not run down during the course of the experiments (n = 38).…”

Section: Propofol Modulation Of Gabaa Receptors Exhibits Membrane Asymentioning

confidence: 99%

The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones

Hales

Lambert

1991

British J Pharmacology

329

226

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University of Dundee, Dundee DD1 9SY1 The interaction of the intravenous general anaesthetic propofol (2,6-diisopropylphenol) with the GABAA receptor has been investigated in voltage-clamped bovine chromaffin cells and rat cortical neurones in cell culture. Additionally, the effects of propofol on the glycine and GABAA receptors of murine spinal neurones were determined. 2 Propofol (1.7-16.8 uM) reversibly and dose-dependently potentiated the amplitude of membrane currents elicited by GABA (100puM) applied locally to bovine chromaffin cells. Intracellular application of propofol (16.8 pM) was ineffective. In rat cortical neurones and murine spinal neurones, extracellular application of 8.4pM and 1.7-16.8/pM propofol respectively produced a potentiation of GABA-evoked currents qualitatively similar to that seen in the bovine chromaffin cell. 3 The potentiation by propofol (1.7,UM) was not associated with a change in the reversal potential of the GABA-evoked whole cell current. On outside-out membrane patches isolated from bovine chromaffin cells, propofol (1.7,UM) had little or no effect on the GABA single channel conductances, but greatly increased the probability of the GABA-gated channel being in the conducting state. 4 The potentiation of GABA-evoked whole cell currents by propofol (1.7 pM) was not influenced by the benzodiazepine antagonist flumazenil (0.3 pM). A concentration of propofol (1.7/pM) that substantially potentiated GABA currents had little effect on currents induced by the activation of the GABAA receptor by pentobarbitone (1 mM). 5 Bath application of propofol (8.4-252 pM), to bovine chromaffin cells voltage clamped at -60 mV, induced an inward current associated with an increase in membrane current noise on all cells sensitive to GABA. Intracellular application of propofol (16.8,UM) was ineffective in this respect. Local application of propofol (600pM) induced whole cell currents with a reversal potential dependent upon the CF-gradient across the cell membrane.6 On outside-out membrane patches formed from bovine chromaffin cells, propofol (30M) induced single channels with mean chord conductances of 29 and 12 pS. The frequency of propofol channels was greatly reduced by coapplication of 1 CM bicuculline. Under identical ionic conditions, GABA (1 pM) activated single channels with mean chord conductances of 33, 16 and 10pS.7 Bath applied propofol (0.84-16.8 juM) dose-dependently potentiated strychnine-sensitive currents evoked by glycine (100,Mm) in murine spinal neurones.8 The relevance of the present results to the general anaesthetic action of propofol is discussed.

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GABA _A -Receptor Function in Hippocampal Cells Is Maintained by Phosphorylation Factors

Cited by 291 publications

References 34 publications

GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea‐pig hippocampal neurones.

GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea‐pig hippocampal neurones.

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones

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GABA A -Receptor Function in Hippocampal Cells Is Maintained by Phosphorylation Factors

Cited by 291 publications

References 34 publications

GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea‐pig hippocampal neurones.

GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea‐pig hippocampal neurones.

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones

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GABA _A -Receptor Function in Hippocampal Cells Is Maintained by Phosphorylation Factors