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Biomedical subjects

M Lazdunski

Publications and source records attributed to M Lazdunski.

At least 217 records · Page 12Linked to original sources
PubMed1992

Nucleotide diphosphates activate the ATP-sensitive potassium channel in mouse skeletal muscle.

Patch-clamp techniques were used to study the effects of internal nucleotide diphosphates on the KATP channel in mouse skeletal muscle. In inside-out patches, application of GDP (100 microM) and ADP (100 microM) reversibly increased the channel activity. In the presence of internal Mg2+ (1 mM), low concentrations of ADP (< 300 microM) enhanced channel activity and high concentrations of ADP (> 300 microM) limited channel opening while GDP activated the channel at all concentrations tested. In the absence of internal Mg2+, ADP decreased channel activity at all concentrations tested while GDP had no noticeable effect at submillimolar concentrations and inhibited channel activity at millimolar concentrations. GDP [beta S] (100 microM), which behaved as a weak GDP agonist in the presence of Mg2+, stimulated ADP-evoked activation whereas it inhibited GDP-evoked activation. The K+ channel opener pinacidil was found to activate the KATP channel but only in the presence of internal GDP, ADP and GDP [beta S]. The results are discussed in terms of the existence of multiple nucleotide binding sites, in charge of the regulation of the KATP channel.

Adenosine Diphosphate↗
PubMed1992

A small-conductance charybdotoxin-sensitive, apamin-resistant Ca(2+)-activated K+ channel in aortic smooth muscle cells (A7r5 line and primary culture).

A small conductance K+ channel was identified in smooth muscle cells of the rat aortic cell line A7r5 and also in rat aortic smooth muscle cells in primary culture, using conventional single-channel recording techniques. The single-channel conductance shows no rectification, either in the range -70 to +40 mV under asymmetrical conditions (9.1 pS), or in the range -100 to +50 mV in symmetrical 150 mM K+ (37 pS). Channel activity is reversibly inhibited by extracellular application of charybdotoxin, with a concentration of 8 nM producing half-maximal inhibition. It is unaffected by apamin or scyllatoxin. Channel activity depends on the presence of free Ca2+ on the cytosolic face of the membrane, with an activation zone between 0.1 and 1 microM. This small-conductance, charybdotoxin-sensitive, Ca(2+)-regulated K+ channel is activated by vasoconstrictors such as vasopressin and endothelin.

Animals↗
PubMed1991

Identification of different receptor types for toxic phospholipases A2 in rabbit skeletal muscle.

Oxyuranus scutellatus scutellatus toxins 1 (OS1) and 2 (OS2) are two phospholipase A2S (PLA2) isolated from the venom of the Australian Taipan snake. Their iodinated derivatives have been used to characterize PLA2 binding sites on rabbit skeletal muscle. Competition and cross-linking experiments indicate that 125I-labelled OS2 binding sites in rabbit skeletal muscle in vivo are distributed into two classes of receptors. One class binds OS2 and OS1 and is insensitive to the bee venom PLA2. It is composed of a 180 kDa binding protein. This class of PLA2 receptor is expressed at a high level in rabbit myotube membranes. The other class of PLA2 receptor identified with 125I-OS2 also binds with high affinity the bee venom PLA2 but not OS1 and is composed of major polypeptides of 34, 48 and 82 kDa. This second class of receptor is similar to the one found in brain membranes. The density of the two classes of receptors varies during muscle development.

Animals↗
PubMed1991

Increase of sodium channels in demyelinated lesions of multiple sclerosis.

Redistribution of sodium channels along demyelinated pathways in multiple sclerosis (MS) could be an important event in restoring conduction prior to other reparative mechanisms such as remyelination. Sodium channels in human multiple sclerosis lesions were identified by quantitative light microscopic autoradiography using tritiated saxitoxin (STX), a highly specific sodium channel ligand. Demyelinated areas in various central nervous system regions containing denuded but vital axons exhibited a high increase of STX-binding sites by up to a factor of 4 as compared to normal human white matter. This important finding could explain aspects of fast clinical remissions and 'silent' MS lesions on functional and morphological properties. Demyelinated axons may functionally reorganize their membranes and adapt properties similar to those of slow conducting unmyelinated nerve fibres which have a higher amount and a more diffuse distribution of STX binding sites. This report is the first description of an altered distribution of voltage-sensitive sodium channels in human multiple sclerosis lesions.

Aged↗
PubMed1991

Two different types of channels are targets for potassium channel openers in Xenopus oocytes.

K+ channel openers elicit K+ currents in follicle-enclosed Xenopus oocytes. The most potent activators are the pinacidil derivatives P1075 and P1060. The rank order of potency to activate K+ currents in follicle-enclosed oocytes was: P1075 (K0.5:5 microM) greater than P1060 (K0.5:12 microM) greater than BRL38227 (lemakalim) (K0.5:77 microM) greater than RP61410 (K0.5:100 microM) greater than (-)pinacidil (K0.5:300 microM). Minoxidil sulfate, nicorandil, RP49356 and diazoxide were ineffective. Activation by the K+ channel openers could be abolished by the antidiabetic sulfonylurea glibenclamide. It was not affected by the blocker of the Ca(2+)-activated K+ channels charybdotoxin. The various K+ channel openers failed to activate glibenclamide-sensitive K+ channels in defolliculated oocytes, but BRL derivatives (K0.5 for BRL38226 is 150 microM) and RP61419 inhibited a background current. The channel responsible for this background current is K+ permeable but not fully selective for K+. It is resistant to glibenclamide. It is inhibited by Ba2+, 4-aminopyridine, Co2+, Ni2+ and La3+.

Animals↗
PubMed1991

MCD peptide and dendrotoxin I activate c-fos and c-jun expression by acting on two different types of K+ channels. A discrimination using the K+ channel opener lemakalim.

Mast cell degranulating (MCD) peptide and Dendrotoxin I (DTXI), two potent hyperexcitability-inducing toxins acting on voltage-dependent potassium channels, induce the expression of both c-fos and c-jun mRNA in i.c.v. treated rats. The distribution of c-fos and c-jun expression has been analyzed by in situ hybridization. The expression is particularly high in the cerebral cortex and hippocampus for both toxins. However differences of expression between MCD and DTXI-treated animals have been observed in hypothalamus and thalamic and amygdaloid nuclei. Moreover, brain areas such as cerebellum which have high amounts of binding sites for both MCD and DTXI do not show any induction of c-fos and c-jun. Lemakalim, a K+ channel opener, prevents the MCD-induced activation of both 'immediate-early genes' in all brain areas but is unable to inhibit the induction of c-fos and c-jun induced by DTXI. These two toxins which are generally believed--from molecular approaches--to act on the same voltage-dependent K+ channel, clearly act in vivo on two distinct classes of channels.

Animals↗
PubMed1991

Anticonvulsant and sleep-waking influences of riluzole in a rat model of absence epilepsy.

Six WAG/Rij rats, an animal model of human absence epilepsy, were injected intraperitoneally with riluzole. At 4 mg/kg, riluzole decreased the number, mean duration and spike-frequency of the spontaneously occurring discharges for 3 h. Riluzole also increased slow wave sleep at the expense of waking. As riluzole at 3 mg/kg decreased the number and spike-frequency of the discharges without inducing a sedative effect, this compound could be of therapeutic interest in human absence epilepsy.

Animals↗
PubMed1991

Hormone-regulated K+ channels in follicle-enclosed oocytes are activated by vasorelaxing K+ channel openers and blocked by antidiabetic sulfonylureas.

Follicular oocytes from Xenopus laevis contain K+ channels activated by members of the recently recognized class of vasorelaxants that include cromakalim and pinacidil and blocked by antidiabetic sulfonylureas, such as glibenclamide. These channels are situated on the adherent follicular cells and are not present in denuded oocytes. Cromakalim-activated K+ channels are also activated by increases in intracellular cAMP, and cAMP-activated K+ channels are blocked by glibenclamide. Although cromakalim and cAMP effects are synergistic, cromakalim activation of K+ channels is drastically reduced or abolished by treatments that stimulate protein kinase C (e.g., muscarinic effectors, phorbol esters). Gonadotropins, known to play an essential role in ovarian physiology, also activate cromakalim and sulfonylurea-sensitive K+ channels. Follicular oocytes constitute an excellent system for studying regulation of cromakalim-sensitive K+ channels that are important in relation to a variety of disease processes, such as cardiovascular dysfunction and asthma, as well as brain function.

Animals↗
PubMed1991

Effect of apamin, a toxin that inhibits Ca(2+)-dependent K+ channels, on learning and memory processes.

Apamin, a neurotoxin extracted from bee venom, specifically binds to a particular class of Ca(2+)-activated K+ channels which are involved in the slow afterhyperpolarization (S-AHP) that follows action potentials in many excitable cells. We tested in mice the effects of apamin on learning and memory processes. The results showed that pre-training injection of apamin accelerated the acquisition of a bar-pressing response but also increased the bar-pressing rates of the animals. This latter result suggests that apamin accelerated acquisition because it increased behavioral activity in general and the number of bar-presses in particular. Post-training apamin injection retroactively and non-contingently facilitated memory processes taking place shortly after training in a bar-pressing task. The lack of an effect of the delayed apamin injection showed that apamin did not act proactively on memory retrieval processes. These results suggest that apamin-sensitive KCa channels may contribute to memory processes.

Animals↗
PubMed1991

Chlorpromazine and related phenothiazines inhibit the ATP-sensitive K+ channel.

Whole-cell, current clamp, single channel recordings and 86Rb+ flux techniques were used to show that phenothiazines inhibit ATP-sensitive K+ channels (KATP) in HIT-T15 beta-cells. Chlorpromazine inhibition was observed when KATP channels were activated by ATP depletion or by direct treatment with a classical KATP channel opener, diazoxide. The order of potency of the phenothiazines tested was chlorpromazine greater than triflupromazine greater than fluphenazine greater than trifluopromazine with IC50 values of 1, 4, 6 and 20 microM, respectively. The inhibition was reversible.

Adenosine Triphosphate↗
PubMed1991

A voltage, calcium, and ATP sensitive non selective cation channel in human colonic tumor cells.

A non selective cation channel has been identified in the human colonic cell lines T84 and HT29D4 using the patch clamp technique. The channel is equally permeable to Na+ and K+, has a linear current-voltage relationship and a conductance of about 20 pS in symmetrical NaCl conditions. The channel is not permeable to chloride or to large organic cations such as N-methyl-D-glucamine. The open probability of the channel is voltage dependent. Cytosolic Ca2+ concentrations higher than 0.1 mM are required to activate the channel. The channel is blocked by cytosolic ATP (1 mM). 3',5-dichlorodiphenylamine-2-carboxylic acid and 5-nitro-2-(3-phenylpropylamino)-benzoic acid inhibit the channel when present on the extracellular side. The block is not voltage dependent. 3',5-dichlorodiphenylamine-2-carboxylic acid is the most potent blocker and completely inhibits channel activity at a concentration of 50 microM. The channel is insensitive to amiloride and derivatives.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Calciseptine, a peptide isolated from black mamba venom, is a specific blocker of the L-type calcium channel.

The venom of the black mamba contains a 60-amino acid peptide called calciseptine. The peptide has been fully sequenced. It is a smooth muscle relaxant and an inhibitor of cardiac contractions. Its physiological action resembles that of drugs, such as the 1,4-dihydropyridines, which are important in the treatment of cardiovascular diseases. Calciseptine, like the 1,4-dihydropyridines, selectively blocks L-type Ca2+ channels and is totally inactive on other voltage-dependent Ca2+ channels such as N-type and T-type channels. To our knowledge, it is the only natural polypeptide that has been shown to be a specific inhibitor of L-type Ca2+ channels.

Amino Acid Sequence↗
PubMed1991

Riluzole prevents hyperexcitability produced by the mast cell degranulating peptide and dendrotoxin I in the rat.

Using electroencephalographic (EEG) recordings in freely moving rats and extracellular neuronal firing-rate recordings in hippocampal slices, we examined the effects of riluzole (RP 54274), a compound with anti-glutamate properties, against the convulsive seizures and the cellular hyperexcitability produced by the mast-cell degranulating peptide (MCD), dendrotoxin I (DTXi) and 4-aminopyridine (4-AP). I.c.v. administration of riluzole (10 nmol) prevented the seizures induced by MCD, and to a lesser extent those due to DIXi, whilst leaving 4-AP seizures unaffected. This effect was also present after oral administration of the compound (4 mg kg-1) and lasted for approximately 6 h. Electrophysiological recordings in vitro confirmed that riluzole dose dependently and reversibly abolished the sustained increase in firing rate induced by both MCD and DTXi in the hippocampus. These results indicate that the anti-epileptic spectrum of riluzole in this model has similarities with, but is not identical to, that of classical potassium channel openers, and differs from that of calcium channel blockers or other glutamate antagonists such as D(-)-2-amino-5-phosphono-valeric acid. However, since MCD releases glutamate, the preventive effect of riluzole in this model may involve direct or indirect interaction with glutamatergic processes.

4-Aminopyridine↗
PubMed1991

Specific hippocampal lesions indicate the presence of sulfonylurea binding sites associated to ATP-sensitive K+ channels both post-synaptically and on mossy fibers.

The density of glibenclamide (GB) binding sites decreases considerably in the dentate gyrus (greater than 80%), the CA1 field (approximately 75%) and the stratum lucidum of CA3 field (approximately 70%) after intradentate colchicine injections in rat hippocampus. The density of GB receptors is unchanged in kainic acid damaged hippocampus. These data show that GB binding sites associated to adenosine triphosphate-sensitive K+ channels are mainly located in granular cells in both pre- and post-synaptic positions. They are present in mossy fibers.

Animals↗
PubMed1991

Activation by cromakalim of pre- and post-synaptic ATP-sensitive K+ channels in substantia nigra.

Membrane potentials and synaptic potentials were recorded using the patch clamp technique from neurons isolated from the substantia nigra. Intracellular perfusion of dopaminergic neurons with an ATP-free solution caused hyperpolarization and inhibition of firing. Intracellular perfusion with a solution containing 2 mM ATP prevented this hyperpolarization, but application of the K+ channel openers cromakalim and pinacidil caused a similar hyperpolarization as well as the disappearance of bicuculline-sensitive synaptic potentials. All these effects were reversed by sulfonylureas, indicating that they are mediated by ATP-sensitive K+ channels. It is concluded that K+ channel openers activate ATP-sensitive K+ channels both presynaptically on GABAergic terminals and postsynaptically on substantia nigra dopaminergic neurons.

Adenosine Triphosphate↗
PubMed1991

K+ efflux pathways and neurotransmitter release associated to hippocampal ischemia: effects of glucose and of K+ channel blockers.

Ischemia of hippocampal slices leads to 86Rb+ efflux and to amino acid neurotransmitter release. This 86Rb+ efflux which corresponds to the massive K+ efflux from neuronal cells observed in ischemic animals is inhibited by glucose (IC50 = 1.7 mM). Glucose also inhibits the ischemia induced liberation of GABA and aspartate. 86Rb+ efflux is insensitive to any type of known blockers for ATP-sensitive, Ca2(+)-sensitive and voltage-sensitive K+ channels.

4-Aminopyridine↗