IndraLab

"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."

"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."

"The observed 2.5-fold higher phosphorylation of cardiac Na + channel (NaV1.5) by CaMKII in HCM samples may have significantly contributed to increase I NaL in HCM cardiomyocytes; this suggests that CaMKII activation is the most relevant cause of I NaL augmentation in HCM cardiac myocytes, although additional mechanisms might be involved (e.g., oxidation of Na + channels)."

"The determinants of peak and late sodium current density are complex, with roles for channel trafficking, CaMKII phosphorylation of SCN5A, subunit interactions, oxidative stress, and metabolic status suggested as potential modifiers."

"CaMKII Phosphorylation of NaV1.5 : novel in vitro sites identified by mass spectrometry and reduced S516 phosphorylation in human heart failure."

"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."

"Phosphorylation of NaV1.5 by CaMKII may also increase pro-arrhythmogenic late Na+ currents [3,11,12,13]."

"It has been described that Nav1.5, Calcium/calmodulin-dependent protein kinase II (CaMKII), and β IV -spectrin form a ternary complex in such a way that β IV -spectrin allows Nav1.5 channels to be pho[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"Our Ca transient study found that FAM13B KD led to decreased Ca amplitude and slower return to baseline (Figure 3), consistent with the pacing-induced pro-arrhythmia state,35 although we did not measure action potential duration in these studies.The determinants of peak and late sodium current density are complex, with roles for channel trafficking, CaMKII phosphorylation of SCN5A, subunit interactions, oxidative stress, and metabolic status suggested as potential modifiers."

"CaMKII Phosphorylation of NaV1.5: novel in vitro sites identified by mass spectrometry and reduced S516 phosphorylation in human heart failure."

"It has been shown that CaMKII phosphorylation of Nav1.5 leads to an increase of late I (I ) and to a shift of voltage dependence of Nav1.5 channel inactivation to hyperpolarized potentials [27]."

"It has been shown that CaMKII phosphorylation of Nav1.5 leads to an increase of late I Na (I NaL ) and to a shift of voltage dependence of Nav1.5 channel inactivation to hyperpolarized potentials [ xref ]."

"However, previous studies have demonstrated that p-CaMKII in its activated state could phosphorylate Nav1.5 under relevant pathological conditions, which leads to chronic INaL augmentation (33,35)."

"However, previous studies have demonstrated that p-CaMKII in its activated state could phosphorylate Nav1.5 under relevant pathological conditions, which leads to chronic INaL augmentation ( xref , xref )."