Agrin regulation of alpha3 sodium-potassium ATPase activity modulates cardiac myocyte contraction.

Full Abstract

Drugs that inhibit Na,K-ATPases, such as digoxin and ouabain, alter cardiac myocyte contractility. We recently demonstrated that agrin, a protein first identified at the vertebrate neuromuscular junction, binds to and regulates the activity of alpha3 subunit-containing isoforms of the Na,K-ATPase in the mammalian brain. Both agrin and the alpha3 Na,K-ATPase are expressed in heart, but their potential for interaction and effect on cardiac myocyte function was unknown. Here we show that agrin binds to the alpha3 subunit of the Na,K-ATPase in cardiac myocyte membranes, inducing tyrosine phosphorylation and inhibiting activity of the pump. Agrin also triggers a rapid increase in cytoplasmic Na(+) in cardiac myocytes, suggesting a role in cardiac myocyte function. Consistent with this hypothesis, spontaneous contraction frequencies of cultured cardiac myocytes prepared from mice in which agrin expression is blocked by mutation of the Agrn gene are significantly higher than in the wild type. The Agrn mutant phenotype is rescued by acute treatment with recombinant agrin. Furthermore, exposure of wild type myocytes to an agrin antagonist phenocopies the Agrn mutation. These data demonstrate that the basal frequency of myocyte contraction depends on endogenous agrin-alpha3 Na,K-ATPase interaction and suggest that agrin modulation of the alpha3 Na,K-ATPase is important in regulating heart function.

Author information

Author/s: Hilgenberg, Lutz G W (LG); Pham, Bryan (B); Ortega, Maria (M); Walid, Saif (S); Kemmerly, Thomas (T); O'Dowd, Diane K (DK); Smith, Martin A (MA);

Affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, USA.

Grants: NS27501 (Agency:NINDS NIH HHS) ; NS33213 (Agency:NINDS NIH HHS) ; (Agency:Howard Hughes Medical Institute)

Journal and publication information

Publication Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: The Journal of biological chemistry (J Biol Chem), published in United States. (Language: eng)

Reference: 2009-Jun; vol 284 (issue 25) : pp 16956-65

Dates: Created 2009/06/15; Completed 2009/10/20;

PMID: 19376779, status: MEDLINE (last retrieval date: 10/20/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Agrin - chemistry; deficiency; genetics; metabolism
Animals
Binding Sites
Cells, Cultured
Cross-Linking Reagents
Fetal Heart - cytology; metabolism
Mice
Mice, Knockout
Multiprotein Complexes

Multiprotein Complexes
Mutation
Myocardial Contraction - genetics; physiology
Myocytes, Cardiac - metabolism
Peptide Fragments - chemistry; genetics; metabolism
Phosphorylation
Protein Binding
Sodium-Potassium-Exchanging ATPase - chemistry; metabolism
Tyrosine - chemistry

Associated Chemicals: Agrin (0) ; Cross-Linking Reagents (0) ; Multiprotein Complexes (0) ; Peptide Fragments (0) ; Tyrosine (55520-40-6) ; Atp1a3 protein, mouse (EC 3.6.1.-) ; Sodium-Potassium-Exchanging ATPase (EC 3.6.3.9)

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