The Cardiac IKs Potassium Channel Macromolecular Complex Includes the Phosphodiesterase PDE4D3

The cardiac I-Ks potassium channel is a macromolecular complex consisting of alpha-(KCNQ1) and beta-subunits (KCNE1) and the A kinase-anchoring protein (AKAP) Yotiao (AKAP-9), which recruits protein kinase A) and protein phosphatase 1 to the channel. Here, we have tested the hypothesis that specific cAMP phosphodiesterase (PDE) isoforms of the PDE4D family that are expressed in the heart are also part of the I-Ks signaling complex and contribute to its regulation by cAMP. PDE4D isoforms co-immunoprecipitated with I-Ks channels in hearts of mice expressing the I-Ks channel. In myocytes isolated from these mice, I-Ks was increased by pharmacological PDE inhibition. PDE4D3, but not PDE4D5, co-immunoprecipitated with the I-Ks channel only in Chinese hamster ovary cells co-expressing AKAP-9, and PDE4D3, but not PDE4D5, co-immunoprecipitated with AKAP-9. Functional experiments in Chinese hamster ovary cells expressing AKAP-9 and either PDE4D3 or PDE4D5 isoforms revealed modulation of the I-Ks response to cAMP by PDE4D3 but not PDE4D5. We conclude that PDE4D3, like protein kinase A and protein phosphatase 1, is recruited to the I-Ks channel via AKAP-9 and contributes to its critical regulation by cAMP.