Idriss M

References (3)

Title : Allosteric inhibition of nicotinic acetylcholine receptors of vertebrates and insects by philanthotoxin - Rozental_1989_J.Pharmacol.Exp.Ther_249_123
Author(s) : Rozental R , Scoble GT , Albuquerque EX , Idriss M , Sherby S , Sattelle DB , Nakanishi K , Konno K , Eldefrawi AT , Eldefrawi ME
Ref : Journal of Pharmacology & Experimental Therapeutics , 249 :123 , 1989
Abstract : The effects of pure philanthotoxin (PhTX), a component of the venom of the wasp Philanthus triangulum, were studied on nicotinic acetylcholine receptors (nAChRs) of vertebrates and insects so as to compare their sensitivities and the mechanism of action of PhTX. Electrophysiological techniques were used on frog muscles and cockroach thoracic ganglia and biochemical techniques were applied to membranes from Torpedo electric organ and honeybee brain. PhTX (1-20 microM) inhibited reversibly the indirectly elicited muscle twitch and reduced the endplate current peak amplitude and its decay time constant in a concentration-dependent manner. In patch clamp studies, PhTX (1-5 microM) when combined with acetylcholine, induced a concentration-dependent decrease in frequency of channel openings and in channel open and burst times. The cockroach fast coxal depressor neuron was inhibited by PhTX in a time- and voltage-dependent manner. The initial rate of binding of [3H]perhydrohistrionicotoxin to Torpedo nAChR in the presence of carbamylcholine was inhibited competitively by PhTX. Binding of alpha-[125I] bungarotoxin to electric organ and honeybee brain membranes was inhibited by PhTX. Binding of [3H]acetylcholine to the electric organ receptor was potentiated by low concentrations of PhTX but inhibited by high concentrations. PhTX, therefore, inhibits both vertebrate and insect nAChRs, which may be important molecular targets for its toxicity. It is suggested that PhTX at high concentration may have some competitive action on nAChR, but it acts mainly as a blocker of the ion channel of the nAChR in its open conformation.
ESTHER : Rozental_1989_J.Pharmacol.Exp.Ther_249_123
PubMedSearch : Rozental_1989_J.Pharmacol.Exp.Ther_249_123
PubMedID: 2468760

Title : Multiple actions of anticholinesterase agents on chemosensitive synapses: molecular basis for prophylaxis and treatment of organophosphate poisoning - Albuquerque_1985_Fundam.Appl.Toxicol_5_S182
Author(s) : Albuquerque EX , Deshpande SS , Kawabuchi M , Aracava Y , Idriss M , Rickett DL , Boyne AF
Ref : Fundamental & Applied Toxicology , 5 :S182 , 1985
Abstract : The present study demonstrates that the reversible and irreversible anti-ChE agents have direct actions on the nicotinic acetylcholine receptor-ionic channel (AChR) and on the locust glutamatergic neuromuscular junction. In addition, the prophylaxis of lethality of organophosphorus anti-ChE compounds was studied. The lethality of VX and sarin was diminished when the rats were pretreated with physostigmine and atropine. The effectiveness of this protection, however, was markedly increased when a ganglionic blocker, either mecamylamine or chlorisondamine, was added, such that all the animals survived after receiving four times a lethal dose of VX. Pretreated animals receiving sarin showed significant recovery of morphological and functional properties of the neuromuscular junction as compared to the damage of structures from animals without pretreatment. Blood ChE inhibition was slightly decreased while brain and muscle AChE levels were significantly recovered (from 98 and 70% to 56 and 32%, respectively) by the pretreatment. This effect may partially explain the protection given by physostigmine but not that afforded by addition of a non-anti-ChE agent. Physostigmine, at concentrations greater than 20 microM, showed both a marked depression of the peak amplitudes of the endplate current (EPC) and a shortening of the decay time constants tau EPC. These effects were mostly due to a direct drug interaction with the nicotinic AChR blocking the ionic channel in its open conformation. Single-channel recordings showed that physostigmine decreases conductance and open times of the channels activated in the presence of ACh and in addition has an agonistic property on the nicotinic AChR. VX, on the other hand, only shortened the open times of ACh-activated channels without affecting the conductance. No agonist property was detected with VX. On glutamatergic synapses, the ChE inhibitors generated spontaneous firing of end-plate potentials (EPPs) and action potentials (APs). This effect was blocked in the presence of low external Ca2+ concentration or tetrodotoxin. It seems that the spontaneous EPP and AP firing resulted from an increased transmitter release induced by an increase in Na+ influx at the presynpatic nerve terminal. Physostigmine and some irreversible ChE inhibitors (VX and DFP) also blocked the postjunctional glutamate receptors. Similar to the nicotinic AChR, this effect was mostly related to a blockade of the open channels. In conclusion, the present studies showed significant protection of rats by physostigmine in combination with some ganglionic antagonists against lethality by organophosphate agents.(ABSTRACT TRUNCATED AT 400 WORDS)
ESTHER : Albuquerque_1985_Fundam.Appl.Toxicol_5_S182
PubMedSearch : Albuquerque_1985_Fundam.Appl.Toxicol_5_S182
PubMedID: 2868960

Title : Phencyclidine (PCP) blocks glutamate-activated postsynaptic currents - Idriss_1985_FEBS.Lett_189_150
Author(s) : Idriss M , Albuquerque EX
Ref : FEBS Letters , 189 :150 , 1985
Abstract : Phencyclidine (PCP) was tested on the metathoracic tibialis muscles of Locusta migratoria. In physiological solution, the peak amplitude of the excitatory postsynaptic currents (EPSCs) evoked by nerve stimulation was linearly related to membrane potential between -50 and -150 mV. The decay time constant of the EPSC (tau EPSC) was exponentially dependent on voltage and decreased with hyperpolarization. The membrane potential change required to produce an e-fold change in tau EPSC was 315 mV. PCP (5-40 microM) produced a concentration-dependent depression of both EPSC peak amplitude and tau EPSC. A slight nonlinearity in the current-voltage relationship could be discerned at high concentrations of PCP. The shortening of the decay time constant of EPSC (tau EPSC) occurred without significant change in the voltage sensitivity observed under control conditions. Under all experimental conditions, the decay of the EPSCs remained a single exponential of time. Fluctuation analysis indicated that 5 microM PCP shortens the lifetime of the glutamate-activated channels by 25.7 +/- 3%. PCP (10-80 microM) did not induced desensitization of the glutamate receptors. These results suggest that PCP interacts with the open conformation of ion channels activated by the glutamate receptor.
ESTHER : Idriss_1985_FEBS.Lett_189_150
PubMedSearch : Idriss_1985_FEBS.Lett_189_150
PubMedID: 2863172