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United States: American Society for Pharmacology and Experimental Therapeutics
Erscheinungsjahr
2002
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
The regulation of cardiac delayed rectifier potassium (Kv) currents by cAMP-dependent protein kinase (PKA) contributes to
the control of blood pressure and heart rate. We investigated the modulation by PKA and protein phosphatases of cloned Kv1.5
channels expressed in Xenopus laevis oocytes. Exposure of oocytes to activators of PKA (100 nM forskolin, 1 mM 8-bromo-cAMP, or 1 mM 3-isobutyl-1-methylxanthine)
had no effect on the amplitude of Kv1.5 currents. Inhibition of PKA by injection of protein kinase A inhibitor peptide or
exposure to myristoylated protein kinase A inhibitor peptide (M-PKI; 100 nM) reduced currents mediated by Kv1.5. M-PKI also
reduced the amplitude of currents mediated by mutated Kv1.5 channels in which the COOH terminal PKA phosphorylation sites
and PSD-95, Disc-large, and ZO-1âbinding domain were removed. The reduction of Kv1.5 currents by M-PKI was attenuated by inhibition
of actin polymerization by 1 μM cytochalasins B and D, but was not affected by 10 μM phalloidin (stabilizes actin filaments)
or 50 μM colchicine (disrupts microtubules). Treatment of oocytes with antisense oligonucleotides against α-actinin-2 abolished
the reduction in Kv1.5 current by M-PKI. These observations suggest that Kv1.5 currents are activated by endogenous PKA in
ârestingâ oocytes and that inhibition of PKA activity reveals the action of endogenous phosphatases. Indeed, injection of
alkaline phosphatase reduced currents mediated by Kv1.5. Further preincubation of oocytes with 1 mM sodium orthovanadate (a
protein tyrosine phosphatase inhibitor) abolished the reduction in Kv1.5 currents by M-PKI. We conclude that currents encoded
by Kv1.5 are regulated by PKA and protein tyrosine phosphatase and that this regulation requires an intact actin cytoskeleton
and α-actinin-2.