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

Desfrère, Luc; Karlsson, Marie; Hiyoshi, Hiromi; Malmersjö, Seth; Nanou, Evanthia; Estrada, Manuel; Miyakawa, Ayako; Lagercrantz, Hugo; Manira, Abdeljabbar El; Lal, Mark; Uhlén, Per

doi:10.1073/pnas.0809253106

Cited by 60 publications

(50 citation statements)

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“…On the other hand, Na/KATPase is known to be a major force in maintaining the resting membrane potential and neuron excitability. Recent studies have further demonstrated that it also regulates cell growth (13,40) and plays a key role in neuronal cell survival/death (41). Thus, our new findings warrant a need of further investigation as to whether the down-regulation of ␣1 Na/K-ATPase contributes to the pathogenesis of NPC1 disease.…”

Section: Discussionmentioning

confidence: 99%

Regulation of α1 Na/K-ATPase Expression by Cholesterol

Chen

et al. 2011

Journal of Biological Chemistry

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We have reported that ␣1 Na/K-ATPase regulates the trafficking of caveolin-1 and consequently alters cholesterol distribution in the plasma membrane. Here, we report the reciprocal regulation of ␣1 Na/K-ATPase by cholesterol. Acute exposure of LLC-PK1 cells to methyl ␤-cyclodextrin led to parallel decreases in cellular cholesterol and the expression of ␣1 Na/K-ATPase. Cholesterol repletion fully reversed the effect of methyl ␤-cyclodextrin. Moreover, inhibition of intracellular cholesterol trafficking to the plasma membrane by compound U18666A had the same effect on ␣1 Na/K-ATPase. Similarly, the expression of ␣1, but not ␣2 and ␣3, Na/K-ATPase was significantly reduced in the target organs of Niemann-Pick type C mice where the intracellular cholesterol trafficking is blocked. Mechanistically, decreases in the plasma membrane cholesterol activated Src kinase and stimulated the endocytosis and degradation of ␣1 Na/K-ATPase through Src-and ubiquitination-dependent pathways. Thus, the new findings, taken together with what we have already reported, revealed a previously unrecognized feed-forward mechanism by which cells can utilize the Src-dependent interplay among Na/K-ATPase, caveolin-1, and cholesterol to effectively alter the structure and function of the plasma membrane. Na/K-ATPase was originally discovered as an active ion transporter residing in the plasma membrane (1). The functional Na/K-ATPase consists of ␣ and ␤ subunits. The ␣ subunit is the catalytic subunit, and four isoforms have been identified. Although the ␣1 isoform is found in all cells, the expression of other isoforms is tissue-specific (2, 3). Na/KATPase is a centrally important ion transporter that is essential for many cellular activities, including maintaining membrane potential and excitability in neurons. Moreover, recent studies indicate that Na/K-ATPase performs many non-pumping functions (4 -8). For example, Na/K-ATPase interacts with Src kinase, forming a functional signaling complex capable of transducing extracellular signals into activation of intracellular kinase cascades (9). Interestingly, the signaling Na/K-ATPase mainly resides in the specialized membrane microdomains called caveolae and interacts with caveolin-1, a caveolae protein marker (7).Caveolin-1 is a 22-kDa protein. In addition to its role in biogenesis of caveolae, caveolin-1 is involved in cholesterol trafficking to and from the plasma membrane (10). Reciprocally, the plasma membrane cholesterol controls the mobility and trafficking of caveolin-1 (11, 12). Interestingly, we have reported that the plasma membrane pool of Na/K-ATPase directly interacts with caveolin-1 (6). Moreover, this interaction not only regulates the mobility and trafficking of caveolin-1 but also plays an important role in maintaining the plasma membrane cholesterol content and in regulating intracellular cholesterol trafficking (8). Thus, to understand the interplay among Na/K-ATPase, cholesterol, and caveolin-1, we examined whether cholesterol regulates the expression of ␣1 Na/KATPase. Our n...

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Section: Discussionmentioning

confidence: 99%

Regulation of α1 Na/K-ATPase Expression by Cholesterol

Chen

et al. 2011

Journal of Biological Chemistry

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“…Particularly, a signaling role of the Na ϩ /K ϩ -ATPase has been demonstrated in regulating synaptic plasticity and dendritic growth in cortical neurons (52). The human ␣ 1 , ␣ 2 , and ␣ 3 isoforms have similar ouabain affinities (25).…”

Section: Discussionmentioning

confidence: 99%

Subunit Isoform Selectivity in Assembly of Na,K-ATPase α-β Heterodimers

Tokhtaeva

Clifford

Kaplan

et al. 2012

Journal of Biological Chemistry

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“…inducing dendritic growth in cortical neurons (12). Evidence for neuronal roles of ATP1␣ 3 was previously found in both human and rat dorsal root ganglia and also observed in rat embryos (embryonic day 21) (13).…”

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confidence: 91%