Products of heme-catalyzed transformation of the arachidonate derivative 12-HPETE open S-type K⁺ channels in Aplysia

In Aplysia mechanosensory neurons, the neuropeptide FMRFamide increases the opening of the background S-K⁺ channel. This action is mediated by activation of arachidonic acid metabolism. Arachidonic acid in Aplysia nervous tissue is transformed through the 12-li-poxygenase pathway to 12-HPETE, which undergoes further metabolism. In intact sensory cells, 12-HPETE simulates the FMRFamide response, raising the question of whether 12-HPETE is the messenger molecule ultimately acting on the S-K⁺ channel. Here we show that in cell-free (inside-out) patches from sensory cells, 12-HPETE fails to modulate the S-K+ channel, but in the presence of hematin (which catalyzes 12-HPETE metabolism), it triggers sharp increases in the channel opening probability. We also found that SKF525A, an inhibitor of the cytochrome P₄₅₀, reduces the response to FMRFamide, arachidonic acid, and 12-HPETE in intact cells. We conclude that a heme-catalyzed transformation of 12-HPETE is necessary and sufficient to promote the opening of the S-K+ channel and a hemecontaining enzyme such as cytochrome P₄₅₀, might play this key role.