Atom-by-atom Tuning of the Electrostatic Potassium-channel Modulator Dehydroabietic Acid

Overview

Journal J Gen Physiol

Specialty Physiology

Date 2018 Apr 8

PMID 29626041

Citations 6

Authors

Malin Silvera Ejneby

Xiongyu Wu

Nina E Ottosson

E Peter Munger

Ingemar Lundstrom

Peter Konradsson

Fredrik Elinder

Affiliations

Soon will be listed here.

Abstract

Dehydroabietic acid (DHAA) is a naturally occurring component of pine resin that was recently shown to open voltage-gated potassium (K) channels. The hydrophobic part of DHAA anchors the compound near the channel's positively charged voltage sensor in a pocket between the channel and the lipid membrane. The negatively charged carboxyl group exerts an electrostatic effect on the channel's voltage sensor, leading to the channel opening. In this study, we show that the channel-opening effect increases as the length of the carboxyl-group stalk is extended until a critical length of three atoms is reached. Longer stalks render the compounds noneffective. This critical distance is consistent with a simple electrostatic model in which the charge location depends on the stalk length. By combining an effective anchor with the optimal stalk length, we create a compound that opens the human K7.2/7.3 (M type) potassium channel at a concentration of 1 µM. These results suggest that a stalk between the anchor and the effector group is a powerful way of increasing the potency of a channel-opening drug.

Citing Articles

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