Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Friday Speaker Abstracts

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.

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