Hydrolysis of inositol phospholipids by phospholipase C is initiated by either receptor stimulation or opening of Ca2+ channels. This was once thought to be the sole mechanism to produce the diacylglycerol that links extracellular signals to intracellular events through activation of protein kinase C. It is becoming clear that agonist-induced hydrolysis of other membrane phospholipids, particularly choline phospholipids, by phospholipase D and phospholipase A2 may also take part in cell signaling. The products of hydrolysis of these phospholipids may enhance and prolong the activation of protein kinase C. Such prolonged activation of protein kinase C is essential for long-term cellular responses such as cell proliferation and differentiation.

https://science.sciencemag.org/content/sci/258/5082/607.full.pdf

Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C

The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this

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The glutamate receptor ion channels

The application of molecular cloning technology to the study of the glutamate receptor system has led to an explosion of knowledge about the structure, expression, and function of this most important fast excitatory transmitter system in the mammalian brain. The first functional ionotropic glutamate receptor was cloned in 1989 (Hollmann et al 1989) , and the results of this molecular-based approach over the past three years are the focus of this review. We discuss the implications of and the new questions raised by this work-which is probably only a glance at this fascinating and complex signaling system found in brains from the snails to man. Glutamate receptors are found throughout the mammalian brain, where they constitute the major excitatory transmitter system. The longest-known and best-studied glutamate receptors are ligand-gated ion channels, also called ionotropic glutamate receptors , which are permeable to cations. They have traditionally been classified into three broad subtypes based upon pharmaco­ logical and electrophysiological data: a-amino-3-hydroxy-5-methyl-4isoxazole propionate (AMPA) receptors, kainate (KA) receptors , and N-methyl-D-aspartate (NMDA) receptors. Recently, however, a family of G protein-coupled glutamate receptors , which are also called metabotropic glutamate or transl -aminocyclopentanel ,3-dicarboxylate (tACPD) recep­ tors, was identified (Sugiyama et al 1987) . (For reviews of the classification and the pharmacological and electrophysiological properties of glutamate receptors see Mayer & Westbrook 1987, Collingridge & Lester 1989, Honore 1989, Monaghan et al 1989, Wroblewski & Danysz 1 989, Hansen &

Cloned Glutamate Receptors

Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophosphonovaleric acid (AP5) does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of hippocampal long-term potentiation (LTP) following brief high-frequency stimulation. We now report that chronic intraventricular infusion of D,L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage, without affecting visual discrimination learning, which is not. The L-isomer of AP5 did not produce behavioural effects. AP5 treatment also suppressed LTP in vivo. These results suggest that NMDA receptors are involved in spatial learning, and add support to the hypothesis that LTP is involved in some, but not all, forms of learning.

Selective impairment of learning and blockade of long-term potentiation by an N -methyl-D-aspartate receptor antagonist, AP5

Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.

We have prepared a series of new and some literature-reported GABA-amides and determined their effect on the activation of GABAA-receptors expressed in CHO cells. Special attention was paid to the purification of the target compounds to remove even traces of GABA contaminations, which may arise from deprotection steps in the synthesis. GABA-amides were previously reported to be partial, full or superagonists. In our hands these compounds were not able to activate GABAA-receptor channels in whole-cell
patch-clamp recordings. New GABA-amides, however, gave moderate activation responses with a clear structure–activity relationship suggesting some of these compounds as promising molecular tools for the functional analysis of GABAA-receptors.

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New GABA amides activating GABAA-receptors.

Activity of hippocampal neurons is regulated by several types of receptors to neuropeptides, hormones and neurotransmitters.14,49 Glutamate is the most prominent neurotransmitter of the fast excitatory synapses in hippocampus and other parts of the mammalian brain. Glutamate receptors include ionotropic and metabotropic families56,60 and the ionotropic ones are divided in two broad classes: N-methyl-D-aspartate (NMDA) and AMPA/kainate.43 NMDA subtype of the glutamate receptor plays an important role in a number of physiological processes concerning neuronal plasticity (long-term potentiation, model of learning on the cellular level)5,43 and various physiological disorders such as ischemic cell death and epilepsy.6,11,51 This subtype is “best characterized of the glutamate receptors and currently the most popular”.4

Modulation of NMDA Currents in Hippocampal Neurones

On May 10th 2010 Platon Grigorevitch Kostyuk sadly left us at the age of 85. He was a talented scientist, a brilliant experimenter, an outstanding organizer of science and an excellent teacher. Platon Kostyuk was born in 1924 in Kiev, Ukraine. He obtained a double education: a graduate of the Kiev University Department of Biology in 1946 and the Kiev Medical Institute in 1949, he became a pioneer in neuroscience, the first in the Soviet Union to use microelectrodes for intracellular recording of electrical signals in neurons. Despite the difficulties for international travel for those living behind the Iron Curtain, he was able to present his work at the International Congress of Physiology in Buenos Aires in 1959 and here met Prof. John Eccles who invited him to work at the University of Canberra in Australia in 1960–1961. This was the start of an outstanding international career, complementing his creative achievements in the Soviet Union. In 1966 P.G. Kostyuk became director of the Bogomoletz Institute of Physiology in Kiev, which he headed for nearly 45 years. Under his direction this Institute became a leading centre for neuroscience, renowned not only in the Soviet Union but also internationally. New directions of research were developed in cell physiology, molecular biophysics and neurophysiology. Several important discoveries were made including the development of a method for intracellular perfusion, evidence for a calcium-dependent conductance in nerve cells and the discovery of new types of ion channels. Elected to the Ukraine Academy of Science in 1969 and Grand Academician of the Soviet Academy of Science in 1974, Kostyuk has also been honoured by many international societies. He is the author of more than 650 articles, 17 monographs and 7 discoveries and was the creator and editor of two scientific journals: “Neurophysiology” and “Neuroscience”. The outstanding career and multifaceted activities of Academician Platon Kostyuk form a pyramid of achievement, at the top of which ride his research in cognition and his enthusiasm for the discovery of the secrets of Nature.

Platon G. Kostyuk: Un survol unique de l’océan du temps (20/08/1924–10/05/2010)

Publisher Summary This chapter discusses a study to analyze fluctuations produced by acetylcholine and its analogs in the neurons of mollusc Limnaea stagnalis. Using the technique of microelectrode voltage clamp in the isolated neurons of mollusc Limnaea stagnalis, the ionic currents of cholinoreceptive membrane were recorded at iontophoretic application of acetylcholine (ACh), carbacholine (CCh), and tetramethyl-ammonium (TMA). Experiments were conducted at room temperature at identified neurons responding to drug applications only with changes in C1 − permeability. Elementary conductance (γ) and average life time (τ) of the Cl − channels were computed using the method of drug-induced membrane fluctuation analysis. It was shown that γ = 3.5 ± 1.55 pS ( n = 20) and did not depend on the drug structure. Potential dependence of τ is very weak: a twofold change of τ proceeds at voltage shift by more than 250 mV. Life time of the Cl − channels depends on the drug structure. For ACh, CCh, and TMA, τ was 17.2; 8.7; 6.4 (msec) respectively; γ and τ did not change in the course of desensitization.

Analysis of fluctuations produced by acetylcholine and its analogues in neurones of mollusc limnaea stagnalis

Glyght is a new photochromic compound described as an effective modulator of glycine receptors at heterologous expression, in brain slices and in zebrafish larvae. Glyght also caused weak inhibition of GABAA-mediated currents in a cell line expressing α1/β2/γ2 GABAA receptors. However, the effects of Glyght on GABAergic transmission in the brain have not been analysed, which does not allow a sufficiently comprehensive assessment of the effects of the compound on the nervous system. Therefore, in this study using whole-cell patch-clamp recording, we analysed the Glyght (100 µM) action on evoked GABAergic inhibitory postsynaptic currents (eIPSCs) in mice hippocampal slices. Two populations of cells were found: the first responded by reducing the GABAergic eIPSCs’ amplitude, whereas the second showed no sensitivity to the compound. Glyght did not affect the ionic currents’ amplitude induced by GABA application, suggesting the absence of action on postsynaptic GABA receptors. Additionally, Glyght had no impact on the paired-pulse modulation of GABAergic eIPSCs, indicating that Glyght does not modulate the neurotransmitter release mechanisms. In the presence of strychnine, an antagonist of glycine receptors, the Glyght effect on GABAergic synaptic transmission was absent. Our results suggest that Glyght can modulate GABAergic synaptic transmission via action on extrasynaptic glycine receptors.

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Piotr Bregestovski

Papers

New GABA amides activating GABAA-receptors.

Modulation of NMDA Currents in Hippocampal Neurones

Platon G. Kostyuk: Un survol unique de l’océan du temps (20/08/1924–10/05/2010)

Analysis of fluctuations produced by acetylcholine and its analogues in neurones of mollusc limnaea stagnalis

Action of the Photochrome Glyght on GABAergic Synaptic Transmission in Mouse Brain Slices