TY - JOUR T1 - Arachidonic Acid Activates Kir2.3 Channels by Enhancing Channel-Phosphatidyl-inositol 4,5-bisphosphate Interactions JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1185 LP - 1194 DO - 10.1124/mol.107.043067 VL - 73 IS - 4 AU - Chuan Wang AU - Uyenlinh L. Mirshahi AU - Boyi Liu AU - Zhanfeng Jia AU - Tooraj Mirshahi AU - Hailin Zhang Y1 - 2008/04/01 UR - http://molpharm.aspetjournals.org/content/73/4/1185.abstract N2 - Kir2.0 channels play a significant role in setting the resting membrane potential, modulating action potential wave form, and buffering extracellular potassium. One member of this family, Kir2.3, is highly expressed in the heart and brain and is modulated by a variety of factors, including arachidonic acid (AA). Using two-electrode voltage clamp and inside-out patch clamp recordings from Xenopus laevis oocytes expressing Kir2.3 channels, we found that AA selectively activated Kir2.3 channels with an EC50 of 0.59 μM and that this activation required phosphatidyl inositol 4,5-bisphosphate (PIP2). We found that AA activated Kir2.3 by enhancing channel-PIP2 interactions as demonstrated by a shift in PIP2 activation curve. EC50 for channel activation by PIP2 were 36 and 12 μM in the absence and presence of AA, respectively. A single point mutation on the channel C terminus that enhanced basal channel-PIP2 interactions reduced the sensitivity of the channel to AA. Effects of AA are mediated through cytoplasmic sites on the channel by increasing the open probability, mainly due to more frequent bursts of opening in the presence of PIP2. Therefore, enhanced interaction with PIP2 is the molecular mechanism for Kir2.3 channel activation by AA. The American Society for Pharmacology and Experimental Therapeutics ER -