TY - JOUR
T1 - Site of anticonvulsant action on sodium channels
T2 - Autoradiographic and electrophysiological studies in rat brain
AU - Worley, P. F.
AU - Baraban, J. M.
PY - 1987
Y1 - 1987
N2 - The anticonvulsants phenytoin and carbamazepine interact allosterically with the batrachotoxin binding site of sodium channels. In the present study, we demonstrate an autoradiographic technique to localize the batrachotoxin binding site on sodium channels in rat brain using [3H]batrachotoxinin-A 20-α-benzoate (BTX-B). Binding of [3H]BTX-B to brain sections is dependent on potentiating allosteric interactions with scorpion venom and is displaced by BTX-B (K(d) ~ 200 nM), aconitine, veratridine, and phenytoin with the same rank order to potencies as described in brain synaptosomes. The maximum number of [3H]BTX-B binding sites in forebrain sections (~ 1 pmol/mg of protein) also agrees with biochemical determinations. Autoradiographic localizations indicate that [3H]BTX-B binding sites are not restricted to cell bodies and axons but are present in synaptics zones throughout the brain. For example, a particularly dense concentration of these sites in the substantia nigra is associated with afferent terminals of teh striatonigral projection. By contrast, myelinated structures possess much lower densities of binding sites. In addition, we present electrophysiological evidence that synaptic transmission, was opposed to axonal conduction, is preferentially sensitive to the action of aconitine and veratridine. Finally, the synaptic block produced by these sodium channel activators is inhibited by phenytoin and carbamazepine at therapeutic anticonvulsant concentrations. Thus, these anticonvlusants may limit seizure spread not only by affecting all-or-none conduction by axonal sodium channels but also by modulating graded aspects of synaptic transmission.
AB - The anticonvulsants phenytoin and carbamazepine interact allosterically with the batrachotoxin binding site of sodium channels. In the present study, we demonstrate an autoradiographic technique to localize the batrachotoxin binding site on sodium channels in rat brain using [3H]batrachotoxinin-A 20-α-benzoate (BTX-B). Binding of [3H]BTX-B to brain sections is dependent on potentiating allosteric interactions with scorpion venom and is displaced by BTX-B (K(d) ~ 200 nM), aconitine, veratridine, and phenytoin with the same rank order to potencies as described in brain synaptosomes. The maximum number of [3H]BTX-B binding sites in forebrain sections (~ 1 pmol/mg of protein) also agrees with biochemical determinations. Autoradiographic localizations indicate that [3H]BTX-B binding sites are not restricted to cell bodies and axons but are present in synaptics zones throughout the brain. For example, a particularly dense concentration of these sites in the substantia nigra is associated with afferent terminals of teh striatonigral projection. By contrast, myelinated structures possess much lower densities of binding sites. In addition, we present electrophysiological evidence that synaptic transmission, was opposed to axonal conduction, is preferentially sensitive to the action of aconitine and veratridine. Finally, the synaptic block produced by these sodium channel activators is inhibited by phenytoin and carbamazepine at therapeutic anticonvulsant concentrations. Thus, these anticonvlusants may limit seizure spread not only by affecting all-or-none conduction by axonal sodium channels but also by modulating graded aspects of synaptic transmission.
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U2 - 10.1073/pnas.84.9.3051
DO - 10.1073/pnas.84.9.3051
M3 - Article
C2 - 2437590
AN - SCOPUS:0023178783
SN - 0027-8424
VL - 84
SP - 3051
EP - 3055
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -