PMID- 26786162
OWN - NLM
STAT- MEDLINE
DCOM- 20170123
LR  - 20181113
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Print)
IS  - 0008-6363 (Linking)
VI  - 110
IP  - 2
DP  - 2016 May 15
TI  - Nav1.5 N-terminal domain binding to alpha1-syntrophin increases membrane density of 
      human Kir2.1, Kir2.2 and Nav1.5 channels.
PG  - 279-90
LID - 10.1093/cvr/cvw009 [doi]
AB  - AIMS: Cardiac excitability and refractoriness are largely determined by the 
      function and number of inward rectifier K(+) channels (Kir2.1-2.3), which are 
      differentially expressed in the atria and ventricles, and Nav1.5 channels. We 
      have focused on how Nav1.5 and Kir2.x function within a macromolecular complex by 
      elucidating the molecular determinants that govern Nav1.5/Kir2.x reciprocal 
      modulation. METHODS AND RESULTS: The results demonstrate that there is an 
      unexpected 'internal' PDZ-like binding domain located at the N-terminus of the 
      Nav1.5 channel that mediates its binding to alpha1-syntrophin. Nav1.5 N-terminal 
      domain, by itself (the 132 aa peptide) (Nter), exerts a 'chaperone-like' effect 
      that increases sodium (I(Na)) and inward rectifier potassium (I(K1)) currents by 
      enhancing the expression of Nav1.5, Kir2.1, and Kir2.2 channels as demonstrated 
      in Chinese hamster ovary (CHO) cells and in rat cardiomyocytes. Site-directed 
      mutagenesis analysis demonstrates that the Nter chaperone-like effect is 
      determined by Serine 20. Nav1.5-Kir2.x reciprocal positive interactions depend on 
      a specific C-terminal PDZ-binding domain sequence (SEI), which is present in 
      Kir2.1 and Kir2.2 channels but not in Kir2.3. Therefore, in human atrial 
      myocytes, the presence of Kir2.3 isoforms precludes reciprocal I(K1)-INa density 
      modulation. Moreover, results in rat and human atrial myocytes demonstrate that 
      binding to alpha1-syntrophin is necessary for the Nav1.5-Kir2.x-positive reciprocal 
      modulation. CONCLUSIONS: The results demonstrate the critical role of the 
      N-terminal domain of Nav1.5 channels in Nav1.5-Kir2.x-reciprocal interactions and 
      suggest that the molecular mechanisms controlling atrial and ventricular cellular 
      excitability may be different.
CI  - Published on behalf of the European Society of Cardiology. All rights reserved. (c) 
      The Author 2016. For permissions please email: journals.permissions@oup.com.
FAU - Matamoros, Marcos
AU  - Matamoros M
AD  - Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 
      28040, Spain Instituto de Investigacion Sanitaria Gregorio Maranon, School of 
      Medicine, Universidad Complutense, Madrid 28040, Spain.
FAU - Perez-Hernandez, Marta
AU  - Perez-Hernandez M
AD  - Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 
      28040, Spain Instituto de Investigacion Sanitaria Gregorio Maranon, School of 
      Medicine, Universidad Complutense, Madrid 28040, Spain.
FAU - Guerrero-Serna, Guadalupe
AU  - Guerrero-Serna G
AD  - Department of Internal Medicine, Center for Arrhythmia Research, University of 
      Michigan, Ann Arbor, MI 48109, USA Department of Molecular and Integrative 
      Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 
      48109, USA.
FAU - Amoros, Irene
AU  - Amoros I
AD  - Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 
      28040, Spain Instituto de Investigacion Sanitaria Gregorio Maranon, School of 
      Medicine, Universidad Complutense, Madrid 28040, Spain.
FAU - Barana, Adriana
AU  - Barana A
AD  - Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 
      28040, Spain Instituto de Investigacion Sanitaria Gregorio Maranon, School of 
      Medicine, Universidad Complutense, Madrid 28040, Spain.
FAU - Nunez, Mercedes
AU  - Nunez M
AD  - Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 
      28040, Spain Instituto de Investigacion Sanitaria Gregorio Maranon, School of 
      Medicine, Universidad Complutense, Madrid 28040, Spain.
FAU - Ponce-Balbuena, Daniela
AU  - Ponce-Balbuena D
AD  - Department of Internal Medicine, Center for Arrhythmia Research, University of 
      Michigan, Ann Arbor, MI 48109, USA Department of Molecular and Integrative 
      Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 
      48109, USA.
FAU - Sacristan, Sandra
AU  - Sacristan S
AD  - Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 
      28040, Spain Instituto de Investigacion Sanitaria Gregorio Maranon, School of 
      Medicine, Universidad Complutense, Madrid 28040, Spain.
FAU - Gomez, Ricardo
AU  - Gomez R
AD  - Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 
      28040, Spain Instituto de Investigacion Sanitaria Gregorio Maranon, School of 
      Medicine, Universidad Complutense, Madrid 28040, Spain.
FAU - Tamargo, Juan
AU  - Tamargo J
AD  - Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 
      28040, Spain Instituto de Investigacion Sanitaria Gregorio Maranon, School of 
      Medicine, Universidad Complutense, Madrid 28040, Spain.
FAU - Caballero, Ricardo
AU  - Caballero R
AD  - Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 
      28040, Spain Instituto de Investigacion Sanitaria Gregorio Maranon, School of 
      Medicine, Universidad Complutense, Madrid 28040, Spain rcaballero@med.ucm.es.
FAU - Jalife, Jose
AU  - Jalife J
AD  - Department of Internal Medicine, Center for Arrhythmia Research, University of 
      Michigan, Ann Arbor, MI 48109, USA Department of Molecular and Integrative 
      Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 
      48109, USA.
FAU - Delpon, Eva
AU  - Delpon E
AD  - Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 
      28040, Spain Instituto de Investigacion Sanitaria Gregorio Maranon, School of 
      Medicine, Universidad Complutense, Madrid 28040, Spain.
LA  - eng
GR  - R01-HL122352/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160119
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (KCNJ2 protein, human)
RN  - 0 (KCNJ2 protein, rat)
RN  - 0 (Kir2.2 channel)
RN  - 0 (Membrane Proteins)
RN  - 0 (Muscle Proteins)
RN  - 0 (NAV1.5 Voltage-Gated Sodium Channel)
RN  - 0 (Potassium Channels, Inwardly Rectifying)
RN  - 0 (SCN5A protein, human)
RN  - 0 (Scn5a protein, rat)
RN  - 0 (syntrophin alpha1)
SB  - IM
CIN - Cardiovasc Res. 2016 May 15;110(2):163-4. PMID: 26984855
MH  - Animals
MH  - Calcium-Binding Proteins/*metabolism
MH  - Cricetinae
MH  - Heart Ventricles/metabolism
MH  - Humans
MH  - Membrane Proteins/*metabolism
MH  - Muscle Proteins/*metabolism
MH  - Mutagenesis, Site-Directed
MH  - Myocytes, Cardiac/metabolism
MH  - NAV1.5 Voltage-Gated Sodium Channel/*metabolism
MH  - Potassium Channels, Inwardly Rectifying/*metabolism
MH  - Rats
PMC - PMC4836625
OTO - NOTNLM
OT  - Inward rectifier current
OT  - Kir2.x
OT  - Sodium current
OT  - alpha1-syntrophin
EDAT- 2016/01/21 06:00
MHDA- 2017/01/24 06:00
PMCR- 2017/05/15
CRDT- 2016/01/21 06:00
PHST- 2015/09/21 00:00 [received]
PHST- 2016/01/13 00:00 [accepted]
PHST- 2016/01/21 06:00 [entrez]
PHST- 2016/01/21 06:00 [pubmed]
PHST- 2017/01/24 06:00 [medline]
PHST- 2017/05/15 00:00 [pmc-release]
AID - cvw009 [pii]
AID - 10.1093/cvr/cvw009 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2016 May 15;110(2):279-90. doi: 10.1093/cvr/cvw009. Epub 2016 Jan 
      19.