Abstract
Cardiomyocytes are highly coordinated cells with multiple proteins organized in micro domains. Minor changes or interference in subcellular proteins can cause major disturbances in physiology. The cardiac sodium channel (NaV1.5) is an important determinant of correct electrical activity in cardiomyocytes which are localized at intercalated discs, T‐tubules and lateral membranes in the form of a macromolecular complex with multiple interacting protein partners. The channel is tightly regulated by post‐translational modifications for smooth conduction and propagation of action potentials. Among regulatory mechanisms, phosphorylation is an enzymatic and reversible process which modulates NaV1.5 channel function by attaching phosphate groups to serine, threonine or tyrosine residues. Phosphorylation of NaV1.5 is implicated in both normal physiological and pathological processes and is carried out by multiple kinases. In this review, we discuss and summarize recent literature about the (a) structure of NaV1.5 channel, (b) formation and subcellular localization of NaV1.5 channel macromolecular complex, (c) post‐translational phosphorylation and regulation of NaV1.5 channel, and (d) how these phosphorylation events of NaV1.5 channel alter the biophysical properties and affect the channel during disease status. We expect, by reviewing these aspects will greatly improve our understanding of NaV1.5 channel biology, physiology and pathology, which will also provide an insight into the mechanism of arrythmogenesis at molecular level.
Highlights
The NaV1.5 channel is the major isoform of the population of sodium channels in human heart responsible for the depolarizing phase of the action potential and conduction of the cardiac impulse
NaV1.5 is encoded by the SCN5A gene, located on the shorter arm of chromosome 3p21.1 The reported half‐life of NaV1.5 is within the range of 17‐ 35 hours,[2,3] and during its life cycle NaV1.5 interacts with multiple protein partners forming a macromolecular complex
We summarize structure and function of the NaV1.5 channel, formation of the macromolecular complex, its subcellular distribution and modulation by phosphorylation
Summary
The NaV1.5 channel is the major isoform of the population of sodium channels in human heart responsible for the depolarizing phase of the action potential and conduction of the cardiac impulse. This family of kinases transduces a diverse range of signals and since the identification of the first member in the 1980s, 11 different isozymes have been identified and categorized into three classes: calcium‐dependent conventional PKCs (α, βI, βII and γ), calcium‐independent novel PKCs (δ, ε, η, θ and μ) and atypical PKCs (ζ and λ).[83] PKC is a downstream effector of several circulating hormones such as angiotensin II (Ang‐II), endothelin and norepinephrine, which upon stimulation cause phosphorylation of several cardiac proteins, activate other kinases and alter gene expression These processes influence impulse conduction and EC‐coupling implicated both in normal physiology and pathological conditions.[84] Like PKA, PKC phosphorylates serine and threonine residues in substrate proteins, but compared to PKA it displays less specificity.[85] Initially it was reported that PKC activators like TPA (phorbol ester) and 1,2‐dioctanoglycerol (diacylglycerol analogue) increased single channel sodium currents and rate of current decay in neonatal rat TABLE 1 Modulation and phosphorylation of NaV1.5 channel. Decreased INa Increased late INa Prolonged QT interval Decreased INa Reduced surface expression of NaV1.5
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
