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1 Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
2 Department of Physiology, University of Texas South west Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9040, USA
3 Department of Biology, Division of Life Sciences, The University of Texas at San Antonio, San Antonio, TX 78249, USA
Voltage-gated Kv7 (KCNQ) channels underlie important K+ currents in many different types of cells, including the neuronal M current, which is thought to be modulated by muscarinic stimulation via depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP2). We studied the role of modulation by angiotensin II (angioII) of M current in controlling discharge properties of superior cervical ganglion (SCG) sympathetic neurons and the mechanism of action of angioII on cloned Kv7 channels in a heterologous expression system. In SCG neurons, which endogenously express angioII AT1 receptors, application of angioII for 2 min produced an increase in neuronal excitability and a decrease in spike-frequency adaptation that partially returned to control values after 10 min of angioII exposure. The increase in excitability could be simulated in a computational model by varying only the amount of M current. Using Chinese hamster ovary (CHO) cells expressing cloned Kv7.2 + 7.3 heteromultimers and AT1 receptors studied under perforated patch clamp, angioII induced a strong suppression of the Kv7.2/7.3 current that returned to near baseline within 10 min of stimulation. The suppression was blocked by the phospholipase C inhibitor edelfosine. Under whole-cell clamp, angioII moderately suppressed the Kv7.2/7.3 current whether or not intracellular Ca2+ was clamped or Ca2+ stores depleted. Co-expression of PI(4)5-kinase in these cells sharply reduced angioII inhibition, but did not augment current amplitudes, whereas co-expression of a PIP2 5'-phosphatase sharply reduced current amplitudes, and also blunted the inhibition. The rebound of the current seen in perforated-patch recordings was blocked by the PI4-kinase inhibitor, wortmannin (50 µM), suggesting that PIP2 re-synthesis is required for current recovery. High-performance liquid chromatographic analysis of anionic phospholipids in CHO cells stably expressing AT1 receptors revealed that PIP2 and phosphatidylinositol 4-phosphate levels are to be strongly depleted after 2 min of stimulation with angioII, with a partial rebound after 10 min. The results of this study establish how angioII modulates M channels, which in turn affects the integrative properties of SCG neurons.
(Received 23 May 2006;
accepted after revision 14 June 2006;
first published online 15 June 2006)
Corresponding author M. S. Shapiro: Department of Physiology, Mail Stop (MS) 7756, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Email: shapirom{at}uthscsa.edu
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