IndraLab

"Although the study reported the novel insight on the binding of calmodulin to Nav1.5 channels specifically at the N-terminal domain, it remains to be elucidated whether similar findings can be proved in a more physiological model, such as cardiomyocytes derived from primary culture or differentiation of pluripotent stem cells."

"Y87C, was reclassified from “Rare variant” (=VUS, Class III) to Likely Pathogenic (P, Class V) because of the experimental evidence of deleterious effect on calmodulin binding with N-terminal domain of the Nav1.5 ( xref )."

"This includes, for example, the CaM-NaV1.5 (IQ-motif) interaction that occurs within the C-lobe of CaM and IQ-motif in α6 of NaV1.5 or the previously mentioned interactions with neurogranin and PITR."

"33 , 34 , 35 While this CaM‐Nav1.5 interaction is altered when the elevation of intracellular Ca2+ concentration, therefore changing the rate of Nav1.5 inactivation."

"33 , 34 , 35 Increasing evidence has shown that at the high level of intracellular Ca2+ concentration, CaM also directly binds to the inactivation gate (IG) of Nav1.5 to destabilize the IG and promote faster recovery from inactivation."

"34 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. [33] [34] [35] While this CaM-Nav1.5 interaction is altered when the elevation of intracellular Ca 2+ concentration, therefore changing the rate of Nav1.5 inactivation. [33] [34] [35] 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. [57] [58] [59] [60] [61] CaMKII not only phosphorylates Nav1.5 at key site S571 62 but also directly interacts with Nav1.5 to regulate the expression and function of Nav1.5."

"The IQ/AA mutation eliminated CaM binding to the carboxyl terminus of both micro1 and hH1 channels."

"24 CAV3 plays a role in prolonging action potential by binding to calmodulin, which binds SCN5A and increases its slow inactivation kinetics in response to regional increase in the concentration of ca[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"24 CAV3 plays a role in prolonging action potential by binding to calmodulin, which binds SCN5A and increases its slow-inactivation kinetics in response to regional increase in the concentration of c[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"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."