Myristoylated peptides potentiate the funny current (If) in sinoatrial myocytes

The funny current, I-f, in sinoatrial myocytes is thought to contribute to the sympathetic fight-or-flight increase in heart rate. I-f is produced by hyperpolarization-activated cyclic nucleotide sensitive-4 (HCN4) channels, and it is widely believed that sympathetic regulation of I-f occurs via direct binding of cAMP to HCN4, independent of phosphorylation. However, we have recently shown that Protein Kinase A (PKA) activity is required for sympathetic regulation of I-f, and that PKA can directly phosphorylate HCN4.(1) In the present study, we examined the effects of a myristoylated PKA inhibitory peptide (myr-PKI) on I-f in mouse sinoatrial myocytes. We found that myr-PKI and another myristoylated peptide potently and specifically potentiated I-f via a mechanism that did not involve PKA inhibition and that was independent of the peptide sequence, Protein Kinase C or phosphatidylinositol-4,5-bisphosphate. The off-target activation of I-f by myristoylated peptides limits their usefulness for studies of pacemaker mechanisms in sinoatrial myocytes.