Abstract
We have shown the synthesized ciguatoxin, CTX3C exhibits multimodal actions on voltage-dependent sodium channels. In this study, we examined the effects of structurelly-modified CTX3C analogs, 51-OH CTX3C, F(8)- and F(10)-51-OH CTX3C: 9-membered F-ring is replaced either with the 8- or 10-membered one, on Nav1.2 and Nav1.8 channels. The maximum condactance (Gmax) of Nav1.2 channels was blocked by 21.6 ± 6.7% (n=3) and 45.0 ± 5.2% (n=3) with 100nM of CTX3C and 51-OH CTX3C, respectively. 10 μM F(8)- and F(10)-analogs suppressed Gmax of Nav1.2 by 22.5 ± 2.5% (n=3) and 24.4 ± 11.4% (n=4), respectively. Moreover, 100 nM CTX3C induced resting conductance of Nav1.2 and Nav1.8, whose effects were estimated as relative conductance (%) to Gmax in the absence of toxin, by 0.14 ± 0.06% (n =3) and 0.86 ± 0.58% (n=5), while 51-OH CTX3C by 0.31 ± 0.21% (n=3) and 1.09 ± 0.12% (n=2), respectively. On the other hand, both 10 μM F(8)- and F(10)-analogs could not induce significant fraction of resting conductance of either of Nav1.2 or Nav1.8 channels. It is crucial to have a 9-membered ring in the middle of the semi-rigid structure comprised of 13 ether rings for CTX analogs to maintain its high biological potency. [J Physiol Sci. 2008;58 Suppl:S70]
