title: Myristoylated peptides potentiate the funny current (I(f)) in sinoatrial myocytes.
abstract: 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. 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.
authors.affiliation: Department of Physiology and Biophysics, University of Colorado, Aurora, CO, USA.
authors.forename: Zhandi
authors.initials: Z
authors.lastname: Liao
authors.forename: Joshua R
authors.initials: JR
authors.lastname: St Clair
authors.forename: Eric D
authors.initials: ED
authors.lastname: Larson
authors.forename: Catherine
authors.initials: C
authors.lastname: Proenza
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism*; D004164:Diphosphonates / Q000737:chemistry; D004594:Electrophysiology / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000166:cytology; D009227:Myristic Acids / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D012849:Sinoatrial Node
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D004164:Diphosphonates; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009227:Myristic Acids; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C