Abstract
Voltage-gated sodium channel alpha and beta subunits expressed in mammalian heart are differentially localized to t-tubules and intercalated disks. Sodium channel beta subunits are multifunctional molecules that participate in channel modulation and cell adhesion. Reversible, receptor-mediated changes in beta1 tyrosine phosphorylation modulate its ability to recruit and associate with ankyrin. The purpose of the present study was to test our hypothesis that tyrosine-phosphorylated beta1 (pYbeta1) and nonphosphorylated beta1 subunits may be differentially localized in heart and thus interact with different cytoskeletal and signaling proteins. We developed an antibody that specifically recognizes pYbeta1 and investigated the differential subcellular localization of beta1 and pYbeta1 in mouse ventricular myocytes. We found that pYbeta1 colocalized with connexin-43, N-cadherin, and Nav1.5 at intercalated disks but was not detected at the t-tubules. Anti-pYbeta1 immunoprecipitates N-cadherin from heart membranes and from cells transfected with beta1 and N-cadherin in the absence of other sodium channel subunits. pYbeta1 does not associate with ankyrinB in heart membranes. N-cadherin and connexin-43 associate with Nav1.5 in heart membranes as assessed by co-immunoprecipitation assays. We propose that sodium channel complexes at intercalated disks of ventricular myocytes are composed of Nav1.5 and pYbeta1 and that these complexes are in close association with both N-cadherin and connexin-43. beta1 phosphorylation appears to regulate its localization to differential subcellular domains.
Highlights
We propose that sodium channel complexes at intercalated disks of ventricular myocytes are composed of Nav1.5 and phosphorylated 1 (pY1) and that these complexes are in close association with both N-cadherin and connexin-43. 1 phosphorylation appears to regulate its localization to differential subcellular domains
We propose that sodium channel complexes at intercalated disks of ventricular myocytes are composed of tetrodotoxin-resistant Nav1.5 and pY1 and that these complexes are in close association with both N-cadherin and connexin-43
Our results suggest that a sodium channel complex consisting of Nav1.5 and pY1 is present at intercalated disks of cardiac myocytes and that this complex is closely associated with N-cadherin and connexin-43
Summary
Tricular myocytes [3, 9]. The tetrodotoxin-sensitive (TTX-S) channels, Nav1.1, Nav1.3, and Nav1.6, colocalize with ␣-sarcomeric actin and are proposed to be expressed in the ttubular system [2, 3]. 1 and 2 associate with Nav1.5 in heart [2], their functional effects on Nav1.5 channels are less clear, and much of the literature remains in disagreement over the importance of these interactions [14] In addition to their roles as channel modulators, 1 and 2 are cell adhesion molecules (CAMs) of the immunoglobulin superfamily [15]. We propose that sodium channel complexes at intercalated disks of ventricular myocytes are composed of tetrodotoxin-resistant Nav1.5 and pY1 and that these complexes are in close association with both N-cadherin and connexin-43. Sodium channels at t-tubules of cardiac myocytes are composed of TTX-S channels, such as Nav1.1 and Nav1.6, and nonphosphorylated 1 subunits These complexes are proposed to be in close association with ankyrinB
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.
