Rozental R

References (3)

Title : A novel agonist binding site on nicotinic acetylcholine receptors - Pereira_1993_J.Recept.Res_13_413
Author(s) : Pereira EF , Alkondon M , Tano T , Castro NG , Froes-Ferrao MM , Rozental R , Aronstam RS , Schrattenholz A , Maelicke A , Albuquerque EX
Ref : J Recept Res , 13 :413 , 1993
Abstract : This report provides evidence that physostigmine (Phy) and benzoquinonium (BZQ) are able to activate nicotinic acetylcholine receptors (nAChRs) through binding site(s) distinct from those of the natural transmitter, ACh. Such findings are in agreement with a second pathway of activation of nAChRs. Receptor activation may be modulated through the novel site, and, consequently, physiological processes involving nicotinic synapses could be controlled. Using patch clamp techniques, single channel currents activated by ACh and anatoxin were recorded from frog interosseal muscle fibers under cell-attached condition and outside-out patches excised from cultured rat hippocampal neurons. Whole cell nicotinic currents were also studied in the cultured neurons. In most of the neurons, nicotinic responses were blocked by the nicotinic antagonists methyllycaconitine (MLA) and alpha-bungarotoxin (alpha-BGT). Evaluation of the effects of Phy and BZQ on the muscle and on the alpha-BGT- and MLA-sensitive neuronal nAChRs demonstrated that both compounds were open channel blockers at these receptors. Furthermore, at low micromolar concentrations, Phy and BZQ activated the nAChRs of all preparations tested, such an effect being unexpectedly resistant to alpha-BGT or MLA. Thus, the nAChRs could be activated via two distinct binding sites: one for ACh and the other for Phy and BZQ. These findings and previous biochemical results led us to suggest that a putative endogenous ligand could bind to the new site and thereby regulate the activation of nAChRs in nicotinic synapses.
ESTHER : Pereira_1993_J.Recept.Res_13_413
PubMedSearch : Pereira_1993_J.Recept.Res_13_413
PubMedID: 8450498

Title : Agonist recognition site of the peripheral acetylcholine receptor ion channel complex differentiates the enantiomers of nicotine - Rozental_1989_J.Pharmacol.Exp.Ther_251_395
Author(s) : Rozental R , Aracava Y , Scoble GT , Swanson KL , Wonnacott S , Albuquerque EX
Ref : Journal of Pharmacology & Experimental Therapeutics , 251 :395 , 1989
Abstract : The multiple actions of nicotine enantiomers at the peripheral nicotinic acetylcholine receptor were evaluated using electrophysiological and biochemical techniques. The alpha-bungarotoxin binding site showed a 6-fold greater affinity for (-)-nicotine than for the (+)-isomer, and this stereoselectivity was reflected in differences in the ability of the alkaloids to activate physiological responses in the forms of single ion channel currents, endplate depolarizations and muscle contractures. (-)-Nicotine was also more potent to induce slow desensitization. In contrast, both (-)- and (+)-nicotine were equipotent as ion channel blockers. Ion channel blockade occurred at effective agonist concentrations for (+)-nicotine but above the effective concentration for (-)-nicotine. The rapid and reversible interaction of nicotine enantiomers with the ion channel occurred at concentrations which implicate a significant contribution of channel blockade to the inhibition of indirect muscle twitch. The agonistic and ion channel blocking effects of the nicotine enantiomers provide important clues regarding the mechanisms by which nicotine may affect central nervous system nicotinic receptors.
ESTHER : Rozental_1989_J.Pharmacol.Exp.Ther_251_395
PubMedSearch : Rozental_1989_J.Pharmacol.Exp.Ther_251_395
PubMedID: 2478693

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