Caffeic Acid Esters Activate TREK-1 Potassium Channels and Inhibit Depolarization-Dependent Secretion

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Abstract
In whole-cell and single-channel patch-clamp recordings from bovine adrenal fasciculata cells, it was discovered that selected caffeic acid derivatives dramatically enhanced the activity of background TREK-1 K+ channels. Cinnamyl 1–3,4-dihydroxy-α-cyanocinnamate (CDC), activated TREK-1 when this agent was applied externally to cells or outside-out patches at concentrations of 5 to 10 μM. Structure/activity studies showed that native bTREK-1 channels were also activated by other caffeic acid esters, including caffeic acid phenethyl ester (CAPE), which contain a benzene or furan ring in the ester side chain. The activation of bTREK-1 by caffeic acid derivatives did not occur through inhibition of lipoxygenases because other potent lipoxygenase inhibitors failed to activate bTREK-1. In bovine adrenal zona fasciculata (AZF) cells, bTREK-1 K+ channels set the resting membrane potential. Inhibition of these channels by corticotropin leads to depolarization-dependent Ca2+ entry and cortisol secretion. CDC, which activates up to thousands of dormant bTREK-1 channels in AZF cells, was found to overwhelm the inhibition of bTREK-1 by corticotropin, reverse the membrane depolarization, and inhibit corticotropin-stimulated cortisol secretion. These results identify selected caffeic acid derivatives as novel K+ channel openers that activate TREK-1 background K+ channels. Because of their ability to stabilize the resting membrane potential and oppose electrical activity and depolarization-dependent Ca2+ entry, these compounds may have therapeutic potential as neuroprotective or cardioprotective agents.