IndraLab

"In a similar manner, the phosphorylation of cardiac Na channel (NaV1.5) by CaMKII alters the inactivation of I [26,47,48], resulting in an increased late Na current (I ), which was found to be markedly larger in human HCM myocytes when compared with non-hypertrophic cardiomyocytes."

"Although CaMKII-dependent Nav1.5 phosphorylation in patients with SDB is a plausible mechanism for AF genesis, detailed underlying molecular mechanisms of CaMKII activation in SDB remain elusive."

"Specifically, CaMKII phosphorylation of NaV1.5 shifts the voltage dependence of inactivation to negative potentials without affecting channel activation, slows recovery from and enhances entry into slower forms of inactivation, and increases INaL (Wagner et al., 2006)."

"In the present study, we used label-free mass spectrometry to assess phosphorylation of human Na(V)1.5 purified from HEK293 cells with full coverage of phosphorylatable sites and identified 23 sites that were phosphorylated by CaMKII in vitro."

"CaMKII Phosphorylation of Na(V)1.5: Novel in Vitro Sites Identified by Mass Spectrometry and Reduced S516 Phosphorylation in Human Heart Failure."

"This work furthers our understanding of the phosphorylation of Na(V)1.5 by CaMKII under normal and disease conditions, provides novel CaMKII target sites for functional validation, and provides the first phospho-proteomic map of full-length human Na(V)1.5."

"In addition, several accessory proteins have been demonstrated to interact directly with the α subunit of Nav1.5 channels (Figure xref ) to form macromolecular complexes with Nav1.5 and modulate the expression, trafficking and biophysical function of Nav1.5 (Table xref ). xref Calmodulin (CaM), a ubiquitously expressed calcium‐binding protein, and CaM‐dependent protein kinase II (CaMKII), an adrenergically activated kinase, serve as important components affecting channel function. xref CaM binds with IQ motif of Nav1.5 carboxyl‐terminal domain (CTD) in Ca 2+ ‐free forms and Ca 2+ ‐bound forms at the basal levels of intracellular Ca 2+ concentration. xref , xref , xref While this CaM‐Nav1.5 interaction is altered when the elevation of intracellular Ca 2+ concentration, therefore changing the rate of Nav1.5 inactivation. xref , xref , xref Increasing evidence has shown that at the high level of intracellular Ca 2+ concentration, CaM also directly binds to the inactivation gate (IG) of Nav1.5 to destabilize the IG and promote faster recovery from inactivation. xref , xref , xref , xref , xref CaMKII not only phosphorylates Nav1.5 at key site S571 xref but also directly interacts with Nav1.5 to regulate the expression and function of Nav1.5. xref On the other hand, protein phosphatase 2A (PP2A) was recently found to interact with the Nav1.5/ankyrin‐G/CaMKII/Βiv‐spectrin macromolecular complex and balance CaMKII‐dependent phosphorylation. xref The CaMKII inhibitor KN93 but not autocamtide‐2‐related inhibitory peptide (AIP) could interrupt the CaM‐IG interaction by forming the ternary complex CaM‐IG‐KN93 and then inhibit Nav1.5 recovery from inactivation without altering the kinetics of inactivation. xref Therefore, determining the effects of accessory proteins and signaling pathways on modulating Nav1.5 provides us with a more comprehensive understanding of Nav1.5 roles in cardiac tissues in both health and disease states and is beneficial for the discovery of potential drug targets."