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1Department of Pharmacology and Experimental Therapeutics and Cardiovascular Institute, Loyola University Chicago, Maywood; and 2Department of Pharmacology, Northwestern University, Chicago, Illinois
Submitted 16 January 2006 ; accepted in final form 25 October 2006
[Arg8]-vasopressin (AVP), at low concentrations (10–500 pM), stimulates oscillations in intracellular Ca2+ concentration (Ca2+ spikes) in A7r5 rat aortic smooth muscle cells. Our previous studies provided biochemical evidence that protein kinase C (PKC) activation and phosphorylation of voltage-sensitive K+ (Kv) channels are crucial steps in this process. In the present study, Kv currents (IKv) and membrane potential were measured using patch clamp techniques. Treatment of A7r5 cells with 100 pM AVP resulted in significant inhibition of IKv. This effect was associated with gradual membrane depolarization, increased membrane resistance, and action potential (AP) generation in the same cells. The AVP-sensitive IKv was resistant to 4-aminopyridine, iberiotoxin, and glibenclamide but was fully inhibited by the selective KCNQ channel blockers linopirdine (10 µM) and XE-991 (10 µM) and enhanced by the KCNQ channel activator flupirtine (10 µM). BaCl2 (100 µM) or linopirdine (5 µM) mimicked the effects of AVP on K+ currents, AP generation, and Ca2+ spiking. Expression of KCNQ5 was detected by RT-PCR in A7r5 cells and freshly isolated rat aortic smooth muscle. RNA interference directed toward KCNQ5 reduced KCNQ5 protein expression and resulted in a significant decrease in IKv in A7r5 cells. IKv was also inhibited in response to the PKC activator 4
-phorbol 12-myristate 13-acetate (10 nM), and the inhibition of IKv by AVP was prevented by the PKC inhibitor calphostin C (250 nM). These results suggest that the stimulation of Ca2+ spiking by physiological concentrations of AVP involves PKC-dependent inhibition of KCNQ5 channels and increased AP firing in A7r5 cells.
potassium channel; signal transduction; membrane potential; calcium; vascular smooth muscle; M current
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