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First published on January 17, 2008; DOI: 10.1124/mol.107.043067

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Received for publication October 31, 2007.
Revised January 9, 2008.
Accepted for publication January 15, 2008.

ARACHIDONIC ACID ACTIVATES KIR2.3 CHANNELS BY ENHANCING CHANNEL-PIP2 INTERACTIONS

Chuan Wang 1, Uyenlinh L Mirshahi 1, Boyi Liu 2, Zhanfeng Jia 2, Tooraj Mirshahi 1*, Hailin Zhang 2

1 Geisinger Clinic 2 Hebei Medical University

* Address correspondence to: E-mail: tmirshahi{at}geisinger.edu

Abstract

Kir2.0 channels play a significant role in setting the resting membrane potential, modulating action potential waveform, 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 oocytes expressing Kir2.3 channels we find that AA selectively activates Kir2.3 channels with an EC50 of 0.59 µM and this activation requires Phosphatidyl-inositol(4,5) bis-phosphate (PIP2). We find that AA activates Kir2.3 by enhancing channel-PIP2 interactions as demonstrated by a shift in PIP2 activation curve. EC50 for channel activation by PIP2 are 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.


Key words: Ion channel regulation, Potassium, Phospholipase C's, Phospholipase A2's, IP3/DAG, Func. analysis receptor/ion channel mutants, Mutagenesis/Chimeric approaches, Single channel kinetics, Oxidative stress, Ischemia/Reperfusion




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