Direct activation of an inwardly rectifying potassium channel by arachidonic acid

Arachidonic acid (AA) is an important constituent of membrane phospholipids and can be liberated by activation of cellular phospholipases. AA modulates a variety of ion channels via diverse mechanisms, including both direct effects by AA itself and indirect actions through AA metabolites. Here, we report excitatory effects of AA on a cloned human inwardly rectifying K+ channel, Kir2.3, which is highly expressed in the brain and heart and is critical in regulating cell excitability. AA potently and reversibly increased Kir2.3 current amplitudes in whole-cell and excised macro-patch recordings (maximal whole-cell response to AA was 258 +/- 21% of control, with an EC50 value of 447 nM at -97 mV). This effect was apparently caused by an action of AA at an extracellular site and was not prevented by inhibitors of protein kinase C, free oxygen radicals, or AA metabolic pathways. Fatty acids that are not substrates for metabolism also potentiated Kir2.3 current. AA had no effect on the currents flowing through Kir2.1, Kir2.2, or Kir2.4 channels. Experiments with Kir2.1/2.3 chimeras suggested that, although AA may bind to both Kir2.1 and Kir2.3, the transmembrane and/or intracellular domains of Kir2.3 were essential for channel potentiation. These results argue for a direct mechanism of AA modulation of Kir2.3.