Combinatorial Interaction of Scorpion Toxins Lqh-2, Lqh-3, and LqhαIT with Sodium Channel Receptor Sites-3
Scorpion α-toxins LqhαIT, Lqh-2, and Lqh-3 are representatives of three groups of α-toxins that differ in their preference for insects and mammals. These α-insect, antimammalian, and α-like toxins bind to voltage-gated sodium channels and slow down channel inactivation. Sodium channel mutagenes...
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Published in | Molecular pharmacology Vol. 65; no. 3; p. 685 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Pharmacology and Experimental Therapeutics
01.03.2004
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Abstract | Scorpion α-toxins LqhαIT, Lqh-2, and Lqh-3 are representatives of three groups of α-toxins that differ in their preference
for insects and mammals. These α-insect, antimammalian, and α-like toxins bind to voltage-gated sodium channels and slow down
channel inactivation. Sodium channel mutagenesis studies using various α-toxins have shown that they interact with receptor
site 3, which is composed mainly of a short stretch of amino-acid residues between S3 and S4 of domain 4. Variation in this
region results in marked differences between various subtypes of sodium channels with respect to their sensitivity to the
three Lqh toxins. We incorporated the S3-S4 linker of domain 4 from hNa V 1.2/hNa V 1.1, hNa V 1.3, hNa V 1.6, and hNa V 1.7 channels as well as individual point mutations into the rNa V 1.4 skeletal muscle sodium channel. Our data show that the affinity of Lqh-3 and LqhαIT to sodium channels is markedly determined
by an aspartate residue (Asp1428 in rNa V 1.4); when mutated to glutamate, as is present in Na V 1.1â1.3 channels, Lqh-3âchannel interactions are abolished. The interaction of Lqh-2 and LqhαIT, however, is strongly reduced
when a lysine residue (Lys1432 in rNa V 1.4) is replaced by threonine (as in hNa V 1.7), whereas this substitution is without effect for Lqh-3. The influence of Lys1432 on Lqh-2 and LqhαIT strongly depends
on the context of the Asp/Glu site at position 1428, giving rise to a wide variety of toxicological phenotypes by means of
a combinatorial mixing and matching of only a few residues in receptor site 3. |
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AbstractList | Scorpion α-toxins LqhαIT, Lqh-2, and Lqh-3 are representatives of three groups of α-toxins that differ in their preference
for insects and mammals. These α-insect, antimammalian, and α-like toxins bind to voltage-gated sodium channels and slow down
channel inactivation. Sodium channel mutagenesis studies using various α-toxins have shown that they interact with receptor
site 3, which is composed mainly of a short stretch of amino-acid residues between S3 and S4 of domain 4. Variation in this
region results in marked differences between various subtypes of sodium channels with respect to their sensitivity to the
three Lqh toxins. We incorporated the S3-S4 linker of domain 4 from hNa V 1.2/hNa V 1.1, hNa V 1.3, hNa V 1.6, and hNa V 1.7 channels as well as individual point mutations into the rNa V 1.4 skeletal muscle sodium channel. Our data show that the affinity of Lqh-3 and LqhαIT to sodium channels is markedly determined
by an aspartate residue (Asp1428 in rNa V 1.4); when mutated to glutamate, as is present in Na V 1.1â1.3 channels, Lqh-3âchannel interactions are abolished. The interaction of Lqh-2 and LqhαIT, however, is strongly reduced
when a lysine residue (Lys1432 in rNa V 1.4) is replaced by threonine (as in hNa V 1.7), whereas this substitution is without effect for Lqh-3. The influence of Lys1432 on Lqh-2 and LqhαIT strongly depends
on the context of the Asp/Glu site at position 1428, giving rise to a wide variety of toxicological phenotypes by means of
a combinatorial mixing and matching of only a few residues in receptor site 3. |
Author | Alfred Hansel Dalia Gordon Enrico Leipold Songqing Lu Stefan H. Heinemann |
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DOI | 10.1124/mol.65.3.685 |
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Snippet | Scorpion α-toxins LqhαIT, Lqh-2, and Lqh-3 are representatives of three groups of α-toxins that differ in their preference
for insects and mammals. These... |
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Title | Combinatorial Interaction of Scorpion Toxins Lqh-2, Lqh-3, and LqhαIT with Sodium Channel Receptor Sites-3 |
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