title: Animal cells connected by nanotubes can be electrically coupled through interposed gap-junction channels.
abstract: Tunneling nanotubes (TNTs) are recently discovered conduits for a previously unrecognized form of cell-to-cell communication. These nanoscale, F-actin-containing membrane tubes connect cells over long distances and facilitate the intercellular exchange of small molecules and organelles. Using optical membrane-potential measurements combined with mechanical stimulation and whole-cell patch-clamp recording, we demonstrate that TNTs mediate the bidirectional spread of electrical signals between TNT-connected normal rat kidney cells over distances of 10 to 70 μm. Similar results were obtained for other cell types, suggesting that electrical coupling via TNTs may be a widespread characteristic of animal cells. Strength of electrical coupling depended on the length and number of TNT connections. Several lines of evidence implicate a role for gap junctions in this long-distance electrical coupling: punctate connexin 43 immunoreactivity was frequently detected at one end of TNTs, and electrical coupling was voltage-sensitive and inhibited by meclofenamic acid, a gap-junction blocker. Cell types lacking gap junctions did not show TNT-dependent electrical coupling, which suggests that TNT-mediated electrical signals are transmitted through gap junctions at a membrane interface between the TNT and one cell of the connected pair. Measurements of the fluorescent calcium indicator X-rhod-1 revealed that TNT-mediated depolarization elicited threshold-dependent, transient calcium signals in HEK293 cells. These signals were inhibited by the voltage-gated Ca(2+) channel blocker mibefradil, suggesting they were generated via influx of calcium through low voltage-gated Ca(2+) channels. Taken together, our data suggest a unique role for TNTs, whereby electrical synchronization between distant cells leads to activation of downstream target signaling.
authors.affiliation: Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Margaret Lin
authors.initials: ML
authors.lastname: Veruki
authors.forename: Nickolay V
authors.initials: NV
authors.lastname: Bukoreshtliev
authors.forename: Espen
authors.initials: E
authors.lastname: Hartveit
authors.forename: Hans-Hermann
authors.initials: HH
authors.lastname: Gerdes
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism; D004560:Electricity; D017629:Gap Junctions / Q000378:metabolism*; D006801:Humans; D043942:Nanotubes; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats
chemical_list: D018031:Connexin 43