An inhibitor of TRPV1 channels isolated from funnel web spider venom

Tetsuya Kitaguchi, Kenton J. Swartz

研究成果: Article査読

55 被引用数 (Scopus)

抄録

Capsaicin receptor channels (TRPV1) are nonselective cation channels that integrate multiple noxious stimuli in sensory neurons. In an effort to identify new inhibitors of these channels we screened a venom library for activity against TRPV1 channels and found robust inhibitory activity in venom from Agelenopsis aperta, a north American funnel web spider. Fractionation of the venom using reversed-phase HPLC resulted in the purification of two acylpolyamine toxins, AG489 and AG505, which inhibit TRPV1 channels from the extracellular side of the membrane. The activity of AG489 was characterized further, and the toxin was found to inhibit TRPV1 channels with a Ki of 0.3 μM at -40 mV. Inhibition of TRPV1 channels by AG489 is strongly voltage-dependent, with relief of inhibition at positive voltages, consistent with the toxin inhibiting the channel through a pore-blocking mechanism. We used scanning mutagenesis throughout the TM5-TM6 linker, a region thought to form the outer pore of TRPV1 channels, to identify pore mutations that alter toxin affinity. Four mutants dramatically decrease toxin affinity and several mutants increase toxin affinity, consistent with the notion that the TM5-TM6 linker forms the outer vestibule of TRPV1 channels and that AG489 is a pore blocker.

本文言語English
ページ(範囲)15544-15549
ページ数6
ジャーナルBiochemistry
44
47
DOI
出版ステータスPublished - 2005 11 29
外部発表はい

ASJC Scopus subject areas

  • Biochemistry

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