Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc

Details

• Alternative Title:
  Nat Commun
• Personal Author:
  Leo-Macias, Alejandra ; Agullo-Pascual, Esperanza ; Sanchez-Alonso, Jose L. ; Keegan, Sarah ; Lin, Xianming ; Arcos, Tatiana ; Feng-Xia-Liang, ; Korchev, Yuri E. ; Gorelik, Julia ; Fenyö, David ; Rothenberg, Eli ; Delmar, Mario
• Description:
  Intercellular adhesion and electrical excitability are considered separate cellular properties. Studies of myelinated fibres, however, show that voltage-gated sodium channels (VGSCs) aggregate with cell adhesion molecules at discrete subcellular locations, such as the nodes of Ranvier. Demonstration of similar macromolecular organization in cardiac muscle is missing. Here we combine nanoscale-imaging (single-molecule localization microscopy; electron microscopy; and 'angle view' scanning patch clamp) with mathematical simulations to demonstrate distinct hubs at the cardiac intercalated disc, populated by clusters of the adhesion molecule N-cadherin and the VGSC NaV1.5. We show that the N-cadherin-NaV1.5 association is not random, that NaV1.5 molecules in these clusters are major contributors to cardiac sodium current, and that loss of NaV1.5 expression reduces intercellular adhesion strength. We speculate that adhesion/excitability nodes are key sites for crosstalk of the contractile and electrical molecular apparatus and may represent the structural substrate of cardiomyopathies in patients with mutations in molecules of the VGSC complex.
• Subjects:
  Cadherins Mice Myocardium NAV1.5 Voltage-Gated Sodium Channel Patch-Clamp Techniques Voltage-Gated Sodium Channels
• Source:
  Nat Commun. 2016; 7.
• Pubmed ID:
  26787348
• Pubmed Central ID:
  PMC4735805
• Document Type:
  Journal Article
• Funding:
  090637/Wellcome Trust/United Kingdom ; 12/18/30088/British Heart Foundation/United Kingdom ; BB/L005816/1/British Heart Foundation/United Kingdom ; NIH C06 RR017528-01-CEM/CE/NCIPC CDC HHS/United States ; NIH S10 OD019994-01/OD/NIH HHS/United States ; NIH S10 RR017291-01/RR/NCRR NIH HHS/United States ; NIH S10 RR029300-01/RR/NCRR NIH HHS/United States ; R01 GM057691/GM/NIGMS NIH HHS/United States ; R01 HL106632/HL/NHLBI NIH HHS/United States ; R01-GM108119/GM/NIGMS NIH HHS/United States ; R01-GM57691/GM/NIGMS NIH HHS/United States ; R01-HL106632/HL/NHLBI NIH HHS/United States ; R21-CA187612/CA/NCI NIH HHS/United States ; R21-GM110385/GM/NIGMS NIH HHS/United States ; WT090594/Wellcome Trust/United Kingdom
• Volume:
  7
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:b0d2debb9d00cb879ad7e887b01b2e2c53faecca192bd41c04db33625eef57dc
• Download URL:
  https://stacks.cdc.gov/view/cdc/40830/cdc_40830_DS1.pdf
• File Type:
  [PDF - 1.96 MB ]