38 / 119
Emerging Concepts in Ion Channel Biophysics
Friday Speaker Abstracts
33
Dietary Oils and BK Channels
Toshinori Hoshi
.
University of Pennsylvania, Philadelphia, PA, USA.
Polyunsaturated omega-3 fatty acids such as docosahexaenoic acid (DHA) are nutraceuticals
enriched in oily fish and are known for their diverse health-promoting properties. We have
recently demonstrated that the large-conductance Ca2+- and voltage-gated Slo1 (BK) channel,
important in regulation of cellular electrical excitability, is a high-affinity direct target of DHA.
The channels are reversibly activated by DHA with a nM-level EC50, and this stimulatory action
contribute to the acute hypotensive action of DHA observed in anesthetized wild-type mice but
not in Slo1 knockout mice. We have manipulated the structures of the ligand DHA and the
effector Slo1 BK channel, incorporating both natural and unnatural amino acids into the channel,
to elucidate the atomic properties required for an optimal DHA-channel interaction. The Z-
configured double bonds near the middle of the nonpolar aliphatic tail group are a critical
determinant of the affinity attribute of the DHA-channel interaction. The efficacy attribute is
determined mainly by the ion-dipole interaction between the electronegative carboxylic acid
head group of DHA and the para-hydroxyl group of a single tyrosine residue (Tyr 318) of the
channel near the ion conduction pathway. Some derivatives of DHA were found to be effective
inhibitors of the channel. All together, we have defined the atomic principles of the fatty acid
action on Slo1 BK channels. Our study shows that the Slo1 BK channel, more specifically the
para-hydroxyl group of Tyr 318, is a promising druggable target amenable to rational drug
design based on naturally occurring compounds.