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Titolo:
Effects of extracellular pH on the interaction of sipatrigine and lamotrigine with high-voltage-activated (HVA) calcium channels in dissociated neurones of rat cortex
Autore:
Hainsworth, AH; Spadoni, F; Lavaroni, F; Bernardi, G; Stefani, A;
Indirizzi:
Osped Santa Lucia, IRCCS, Rome, Italy Osped Santa Lucia Rome ItalyOsped Santa Lucia, IRCCS, Rome, Italy De Montfort Univ, Sch Pharm, Pharmacol Sect, Leicester LE1 9BH, Leics, England De Montfort Univ Leicester Leics England LE1 9BH LE1 9BH, Leics, England Univ Roma Tor Vergata, Neurol Clin, I-00133 Rome, Italy Univ Roma Tor Vergata Rome Italy I-00133 eurol Clin, I-00133 Rome, Italy
Titolo Testata:
NEUROPHARMACOLOGY
fascicolo: 6, volume: 40, anno: 2001,
pagine: 784 - 791
SICI:
0028-3908(200105)40:6<784:EOEPOT>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
NEUROPROTECTIVE AGENT BW619C89; CA2+ CHANNELS; CORTICAL-NEURONS; SODIUM-CHANNEL; NA+ CHANNELS; EXTERNAL PH; GATED NA+; CURRENTS; INHIBITION; MODULATION;
Keywords:
calcium channels; neuroprotection; 619C89; sipatrigine; lamotrigine; activation;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
36
Recensione:
Indirizzi per estratti:
Indirizzo: Stefani, A Osped Santa Lucia, IRCCS, Rome, Italy Osped Santa Lucia Rome Italy Santa Lucia, IRCCS, Rome, Italy
Citazione:
A.H. Hainsworth et al., "Effects of extracellular pH on the interaction of sipatrigine and lamotrigine with high-voltage-activated (HVA) calcium channels in dissociated neurones of rat cortex", NEUROPHARM, 40(6), 2001, pp. 784-791

Abstract

Acidic extracellular pH reduced high-voltage-activated (HVA) currents in freshly isolated cortical pyramidal neurones of adult rats, shifting activation to more positive voltages (V-1/2=-18 mV at pH 7.4, -11 mV at pH 6.4). Sipatrigine inhibited HVA currents, with decreasing potency at acidic pH (IC50 8 muM at pH 7.4, 19 muM at pH 6.4) but the degree of maximal inhibition was >80% in all cases (pH 6.4-8.0). Sipatrigine has two basic groups (pK(A)values 4.2, 7.7) and at pH 7.4 is 68% in monovalent cationic form and 32% uncharged. From simple binding theory, the pH dependence of sipatrigine inhibition indicates a protonated group with pK(A) 6.6. Sipatrigine (50 muM) shifted the voltage dependence of channel activation at pH 7.4 (-7.6 mV shift) but not at pH 6.4. Lamotrigine has one basic site (pK(A) 5.5) and inhibited 34% of the HVA current, with similar potency over the pH range 6.4-7.4 (IC50 7.5-9 muM). These data suggest that the sipatrigine binding site on HVA calcium channels binds both cationic and neutral forms of sipatrigine, interacts with a group with pK(A)=6.6 and with the channel activation process, and differs from that for lamotrigine. Crown Copyright (C) 2001 Published by Elsevier Science Ltd. All rights reserved.

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Documento generato il 13/07/20 alle ore 07:51:49