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Na,K-ATPase signal transduction triggers CREB activation and dendritic growth.

ABSTRACT: Dendritic growth is pivotal in the neurogenesis of cortical neurons. The sodium pump, or Na,K-ATPase, is an evolutionarily conserved protein that, in addition to its central role in establishing the electrochemical gradient, has recently been reported to function as a receptor and signaling mediator. Although a large body of evidence points toward a dual function for the Na,K-ATPase, few biological implications of this signaling pathway have been described. Here we report that Na,K-ATPase signal transduction triggers dendritic growth as well as a transcriptional program dependent on cAMP response element binding protein (CREB) and cAMP response element (CRE)-mediated gene expression, primarily regulated via Ca(2+)/calmodulin-dependent protein (CaM) kinases. The signaling cascade mediating dendritic arbor growth also involves intracellular Ca(2+) oscillations and sustained phosphorylation of mitogen-activated protein (MAP) kinases. Thus, our results suggest a novel role for the Na,K-ATPase as a modulator of dendritic growth in developing neurons.

SUBMITTER: Desfrere L

PROVIDER: S-EPMC2629786 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Na,K-ATPase signal transduction triggers CREB activation and dendritic growth.

Desfrere Luc L Karlsson Marie M Hiyoshi Hiromi H Malmersjö Seth S Nanou Evanthia E Estrada Manuel M Miyakawa Ayako A Lagercrantz Hugo H El Manira Abdeljabbar A Lal Mark M Uhlén Per P

Proceedings of the National Academy of Sciences of the United States of America 20090122 7

Dendritic growth is pivotal in the neurogenesis of cortical neurons. The sodium pump, or Na,K-ATPase, is an evolutionarily conserved protein that, in addition to its central role in establishing the electrochemical gradient, has recently been reported to function as a receptor and signaling mediator. Although a large body of evidence points toward a dual function for the Na,K-ATPase, few biological implications of this signaling pathway have been described. Here we report that Na,K-ATPase signal ...[more]

PMID: 19164762

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Project description:BackgroundIt has not been possible to study the pumping and signaling functions of Na/K-ATPase independently in live cells.ResultsBoth cell-free and cell-based assays indicate that the A420P mutation abolishes the Src regulatory function of Na/K-ATPase.ConclusionA420P mutant has normal pumping but not signaling function.SignificanceIdentification of Src regulation-null mutants is crucial for addressing physiological role of Na/K-ATPase. The α1 Na/K-ATPase possesses both pumping and signaling functions. However, it has not been possible to study these functions independently in live cells. We have identified a 20-amino acid peptide (Ser-415 to Gln-434) (NaKtide) from the nucleotide binding domain of α1 Na/K-ATPase that binds and inhibits Src in vitro. The N terminus of NaKtide adapts a helical structure. In vitro kinase assays showed that replacement of residues that contain a bulky side chain in the helical structure of NaKtide by alanine abolished the inhibitory effect of the peptide on Src. Similarly, disruption of helical structure by proline replacement, either single or in combination, reduced the inhibitory potency of NaKtide on Src. To identify mutant α1 that retains normal pumping function but is defective in Src regulation, we transfected Na/K-ATPase α1 knockdown PY-17 cells with expression vectors of wild type or mutant α1 carrying Ala to Pro mutations in the region of NaKtide helical structure and generated several stable cell lines. We found that expression of either A416P or A420P or A425P mutant fully restored the α1 content and consequently the pumping capacity of cells. However, in contrast to A416P, either A420P or A425P mutant was incapable of interacting and regulating cellular Src. Consequently, expression of these two mutants caused significant inhibition of ouabain-activated signal transduction and cell growth. Thus we have identified α1 mutant that has normal pumping function but is defective in signal transduction.

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Na,K-ATPase signal transduction triggers CREB activation and dendritic growth.

Publications

Na,K-ATPase signal transduction triggers CREB activation and dendritic growth.

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