FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2811017811> ?p ?o ?g. }

• W2811017811 abstract "The study by Bouzinova et al1 published in this issue of Acta Physiologica attracted my attention due to a particular issue that fits well into a series of recent observations and may set a trend: ion transporters do not only carry ions through biological membranes but function also as signal transducers. For a long time, ion transporters, that is pumps, exchangers and channels, have been considered to be exclusively responsible for transferring ions, unable to pass the membrane lipid bilayer on their own, from one side of the membrane to the other. However, there is a growing number of studies, suggesting that ion transporters are multifunctional proteins that have an additional role as signal transducers independent of ion transfer. The process of conceptual change in relation to the functional role of ion transporters is quite nicely reflected in previous publications of the group presenting the study by Bouzinova et al1 published in this issue of Acta Physiologica. Thus, in 2007 the group addressed the question how an interaction between the Na+,K+-ATPase and the Na+,Ca2+-exchanger, well known as some of the most important regulators of ion homeostasis, affects the communication between vascular smooth muscle cells.2 It was concluded that inhibition of the Na+,K+-ATPase by its blocker ouabain results in a reduction in the transmembrane Na+ gradient, leading to an attenuation of Na+,Ca2+-exchanger activity and a subsequent increase in the local intracellular calcium concentration. The latter was supposed to inhibit gap junctions, resulting in desynchronization of smooth muscle cells and thereby in a reduction in vasomotion. Thus, this study promoted the idea of a functional interaction between spatially closely related proteins, that is of protein—protein functional interaction in so-called signalosomes. In a subsequent study, the question was addressed whether the α2-isoform of the Na+,K+-ATPase is involved in the control of intercellular communication and vascular tone in small arteries.3 The results showed that an in vivo knockdown of the α2-isoform of the Na+,K+-ATPase, associated with downregulation of the Na+,Ca2+-exchanger, reduces intercellular communication as well as the EDHF response. Thus, this study confirmed the findings of the preceding study about the functional interaction between the Na+,K+-ATPase and the Na+,Ca2+-exchanger in signalosomes and extended them by identifying the Na+,K+-ATPase isoform involved. A conceptual change regarding the functional role of the Na+,K+-ATPase has become evident for the first time in a more recent publication by this group. Although the signalosome mechanism of a functional interaction between the Na+,K+-ATPase and the Na+,Ca2+-exchanger seems to provide a sufficient explanation for the vasoactive effect of Na+,K+-ATPase inhibitors like ouabain, the authors stayed curious and noticed novel facts that challenged prevailing ideas. In an effort to join old findings and new discoveries, they focused on the question whether Src kinase is involved in the regulation of intercellular communication by the Na+,K+-ATPase.4 To address this question, the authors used a specific tool, pNaKtide, a peptide composed of the Na+,K+-ATPase N-terminal amino acid sequence suggested being involved in the interaction with Src-kinase. The study showed that inhibition of the Na+,K+-ATPase by its blocker ouabain results in Src phosphorylation and activation as well as in Connexin43 phosphorylation and conductance reduction with subsequent attenuation of intercellular communication and vasomotion. It was concluded that cardiotonic steroids, for example ouabain, activate a Na+,K+-ATPase-dependent Src-kinase signalling pathway independent of ion transport to regulate intercellular communication, a mechanism considered to complement the signalosome mechanism described before. What additional insight was obtained in the new study by Bouzinova et al1 published in this issue of Acta Physiologica? This investigation carried forward the idea that the Na+,K+-ATPase may function as a signal transducer independent of ion transport. It is the merit of this study to search for additional evidence supporting the signal transducer idea by addressing the question whether the Na+,K+-ATPase-Src kinase signalling pathway mediates the acute ouabain-induced enhancement of agonist-induced contraction. It was found (a) that acute application of ouabain, the Na+,K+-ATPase-inhibitor, strengthened agonist-induced contractions in rat mesenteric arteries in vitro, an effect independent of the endothelium; (b) that ouabain increased the sensitivity of the contractile apparatus to calcium and that this effect was associated with MYPT1 phosphorylation; (c) that both effects of ouabain were abolished by the Src-kinase inhibitor PP2 as well as by pNaKtide, the peptide interfering with the interaction between Src-kinase and the Na+,K+-ATPase; and (d) that downregulation of the Na+,K+-ATPase α2-isoform in vivo removed the effect of ouabain and Src-kinase inhibition on vessel contraction. Altogether, as the effect of ouabain was not consistent with an inhibition of Na+,K+-ATPase ion transport activity or Na+,Ca2+-exchanger—mediated effects on calcium signalling, it was concluded that ouabain increases agonist-induced contractions of rat mesenteric small arteries by an α2-Na+,K+-ATPase—mediated Src-kinase activation followed by calcium sensitization via MYPT1 phosphorylation. Thus, the Na+,K+-ATPase functions as a signal transducer independent of ion transport in vessel contractions. It should be mentioned that the function of the Na+,K+-ATPase as a signal transducer independent of ion transport is consistent with a number of observations on other ion transporters. Thus, aside from ion pumps like the Na+,K+-ATPase, ion channels have been found to operate as bifunctional proteins: (a) L-type voltage-activated calcium channels activate the Ras-/mitogen-activated protein kinase (MAPK) pathway that targets genes involved in neuronal survival and plasticity5; (b) Channels underlying the neuronal transient potassium current increase a hyperpolarization-activated inward current, and this effect was independent of ion channel activity of the transient potassium channels6; (c) A transient receptor potential channel, TRP-PLIK, is an ion channel as well as a protein kinase7; (d) Large conductance calcium-dependent potassium channels bind Src kinase and cAMP-dependent protein kinase, thus serving as a scaffold for these kinases8; (e) Ether-a-go-go potassium channels affect cell proliferation mediated by p38 MAP kinases. This signalling did not require ion flux but was related to voltage sensor—dependent conformational changes of the channel9; and (f) vascular smooth muscle voltage-gated calcium channels couple to G-proteins and phospholipase C resulting in IP3-mediated calcium release and contraction, an effect called the metabotropic role of voltage-gated calcium channels.10, 11 These studies demonstrate that ion transporters do not only serve as carriers for ion movements through biological membranes but also possess a second, unrelated function as signal transducers. In this role, they are involved in transcriptional regulation, protein scaffolding, cell adhesion, cell division as well as intercellular and intracellular signalling. It is the merit of the new study by Bouzinova et al1 published in this issue of Acta Physiologica, together with the previous reports of this group, to have provided two important impulses: (a) specifically, the study extends previous observations of the role of the Na+,K+-ATPase in vascular smooth muscle to a new signal transducing function and (b) generally, the study strengthens the concept of the role of ion transporters as signal transducers independent of ion transport. Thus, this study by Bouzinova et al will, hopefully, ignite more research addressing ion transporters as signal transducers not only in vascular smooth muscle but also in many other organs and tissues under physiological as well as disease conditions. None declared." @default.
• W2811017811 created "2018-07-10" @default.
• W2811017811 creator A5002685729 @default.
• W2811017811 date "2018-07-13" @default.
• W2811017811 modified "2023-10-14" @default.
• W2811017811 title "The second life of ion transporters as signal transducers" @default.
• W2811017811 cites W1581890644 @default.
• W2811017811 cites W1977378747 @default.
• W2811017811 cites W1997808089 @default.
• W2811017811 cites W2005535029 @default.
• W2811017811 cites W2034998738 @default.
• W2811017811 cites W2052998178 @default.
• W2811017811 cites W2076555662 @default.
• W2811017811 cites W2086133687 @default.
• W2811017811 cites W2092262479 @default.
• W2811017811 cites W2580530765 @default.
• W2811017811 cites W2791562934 @default.
• W2811017811 doi "https://doi.org/10.1111/apha.13155" @default.
• W2811017811 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29938912" @default.
• W2811017811 hasPublicationYear "2018" @default.
• W2811017811 type Work @default.
• W2811017811 sameAs 2811017811 @default.
• W2811017811 citedByCount "1" @default.
• W2811017811 countsByYear W28110178112019 @default.
• W2811017811 crossrefType "journal-article" @default.
• W2811017811 hasAuthorship W2811017811A5002685729 @default.
• W2811017811 hasBestOaLocation W28110178111 @default.
• W2811017811 hasConcept C104317684 @default.
• W2811017811 hasConcept C121332964 @default.
• W2811017811 hasConcept C12554922 @default.
• W2811017811 hasConcept C149011108 @default.
• W2811017811 hasConcept C199360897 @default.
• W2811017811 hasConcept C24890656 @default.
• W2811017811 hasConcept C2779843651 @default.
• W2811017811 hasConcept C41008148 @default.
• W2811017811 hasConcept C55493867 @default.
• W2811017811 hasConcept C56318395 @default.
• W2811017811 hasConcept C70721500 @default.
• W2811017811 hasConcept C86803240 @default.
• W2811017811 hasConceptScore W2811017811C104317684 @default.
• W2811017811 hasConceptScore W2811017811C121332964 @default.
• W2811017811 hasConceptScore W2811017811C12554922 @default.
• W2811017811 hasConceptScore W2811017811C149011108 @default.
• W2811017811 hasConceptScore W2811017811C199360897 @default.
• W2811017811 hasConceptScore W2811017811C24890656 @default.
• W2811017811 hasConceptScore W2811017811C2779843651 @default.
• W2811017811 hasConceptScore W2811017811C41008148 @default.
• W2811017811 hasConceptScore W2811017811C55493867 @default.
• W2811017811 hasConceptScore W2811017811C56318395 @default.
• W2811017811 hasConceptScore W2811017811C70721500 @default.
• W2811017811 hasConceptScore W2811017811C86803240 @default.
• W2811017811 hasIssue "1" @default.
• W2811017811 hasLocation W28110178111 @default.
• W2811017811 hasLocation W28110178112 @default.
• W2811017811 hasOpenAccess W2811017811 @default.
• W2811017811 hasPrimaryLocation W28110178111 @default.
• W2811017811 hasRelatedWork W1972327185 @default.
• W2811017811 hasRelatedWork W1980475811 @default.
• W2811017811 hasRelatedWork W1999283874 @default.
• W2811017811 hasRelatedWork W2027703852 @default.
• W2811017811 hasRelatedWork W2030264254 @default.
• W2811017811 hasRelatedWork W2313673198 @default.
• W2811017811 hasRelatedWork W2350246041 @default.
• W2811017811 hasRelatedWork W26309568 @default.
• W2811017811 hasRelatedWork W2738393748 @default.
• W2811017811 hasRelatedWork W3023872024 @default.
• W2811017811 hasVolume "224" @default.
• W2811017811 isParatext "false" @default.
• W2811017811 isRetracted "false" @default.
• W2811017811 magId "2811017811" @default.
• W2811017811 workType "article" @default.