Docosahexaenoic acid block of neuronal voltage-gated K+ channels: subunit selective antagonism by zinc.
The omega-3 polyunsaturated fatty acid docosahexaenoic acid is highly enriched in neuronal membranes, and several studies suggest that DHA is critical for neuronal development. We have investigated the effects of exogenously applied DHA on voltage-gated K+ channels using patch-clamp techniques. DHA produced a concentration-dependent inhibition of the sustained outward current in isolated neocortical neurons. This blocking action was examined in more detail with two cloned neuronal K+ channels (Kv1.2 and Kv3.1a) expressed in mammalian fibroblasts. DHA produced a potent inhibition of depolarization-activated K+ currents from cells expressing these channels (Kd values, 1.8 +/- 0.1 muM and 690 +/- 60 nM, for Kv1.2 and Kv3.1a, respectively, at +40 mV). The DHA block of both channel types was rapidly reversed (approximately 2 sec) by bovine serum albumin, which binds the fatty acid. Micromolar concentrations of extracellular Zn2+ non-competitively antagonized DHA inhibition of Kv1.2 channels, whereas there was little effect on DHA block of Kv3.1a channels. Experiments with membrane patches from Kv1.2 transfected cells demonstrated that the DHA block occurred from the outside, suggesting that the fatty acid interacts directly with an external domain of the ion channel. DHA may serve as a local messenger molecule that selectively modulates the activity of certain voltage-gated K+ channels in a Zn2(+)-dependent fashion.
Poling
J S
JS
Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol and Abuse and Alcoholism, Rockville, MD 20852, USA.
Vicini
S
S
Rogawski
M A
MA
Salem
N
N
D000818:Animals; D000831:Animals, Newborn; D016718:Arachidonic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D051663:Kv1.2 Potassium Channel; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000096:biosynthesis / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D017207:Rats, Sprague-Dawley; D051670:Shaw Potassium Channels; D015032:Zinc / Q000494:pharmacology*
C496970:Kcna2 protein, mouse; C496972:Kcna2 protein, rat; C490839:Kcnc1 protein, mouse; C098254:Kcnc1 protein, rat; D051663:Kv1.2 Potassium Channel; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051670:Shaw Potassium Channels; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D015032:Zinc