@article {Mason285, author = {H. S. Mason and M. J. Latten and L. D. Godoy and B. Horowitz and J. L. Kenyon}, title = {Modulation of Kv1.5 Currents by Protein Kinase A, Tyrosine Kinase, and Protein Tyrosine Phosphatase Requires an Intact Cytoskeleton}, volume = {61}, number = {2}, pages = {285--293}, year = {2002}, doi = {10.1124/mol.61.2.285}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 inXenopus 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-1{\textendash}binding 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 {\textquotedblleft}resting{\textquotedblright} 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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/61/2/285}, eprint = {https://molpharm.aspetjournals.org/content/61/2/285.full.pdf}, journal = {Molecular Pharmacology} }