AKAP proteins anchor cAMP-dependent protein kinase to KvLQT1/IsK channel complex

In cardiac myocytes, the slow component of the delayed rectifier K+ current (I-Ks) is regulated by cAMP. Elevated cAMP increases I-Ks amplitude, slows its deactivation kinetics, and shifts its activation curve. At the molecul ar level, I-Ks channels are composed of KvLQT1/IsK complexes. In a variety of mammalian heterologous expression systems maintained at physiological te mperature, we explored cAMP regulation of recombinant KvLQT1/IsK complexes. In these systems, KvLQT1/IsK complexes were totally insensitive to cAMP re gulation. cAMP regulation was not restored by coexpression with the dominan t negative isoform of KvLQT1 or with the cystic fibrosis transmembrane regu lator. In contrast, coexpression of the neuronal A kinase anchoring protein (AKAP)79, a fragment of a cardiac AKAP (mAKAP), or cardiac AKAP15/18 resto red cAMP regulation of KvLQT1/IsK complexes inasmuch as cAMP stimulation in creased the I-Ks amplitude, increased its deactivation time constant, and n egatively shifted its activation curve. However, in cells expressing an AKA P, the effects of cAMP stimulation on the I-Ks amplitude remained modest co mpared with those previously reported in cardiac myocytes. The effects of c AMP stimulation were fully prevented by including the Ht31 peptide (a globa l disruptor of protein kinase A anchoring) in the intracellular medium. We concluded that cAMP regulation of I-Ks requires protein kinase A anchoring by AKAPs, which therefore participate with the channel protein complex unde rlying I-Ks.