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 modulate s a variety of ion channels via diverse mechanisms, including both direct e ffects by AA itself and indirect actions through AA metabolites. Here, we r eport excitatory effects of AA on a cloned human inwardly rectifying K+ cha nnel, Kir2.3, which is highly expressed in the brain and heart and is criti cal in regulating cell excitability. AA potently and reversibly increased K ir2.3 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 prote in kinase C, free oxygen radicals, or AA metabolic pathways. Fatty acids th at are not substrates for metabolism also potentiated Kir2.3 current. AA ha d no effect on the currents flowing through Kir2.1, Kir2.2, or Kir2.4 chann els. Experiments with Kir2.1/2.3 chimeras suggested that, although AA may b ind to both Kir2.1 and Kir2.3, the transmembrane and/or intracellular domai ns of Kir2.3 were essential for channel potentiation. These results argue f or a direct mechanism of AA modulation of Kir2.3.