Details

Autor(en) / Beteiligte

• Shcheynikov, Nikolay
• Son, Aran
• Hong, Jeong Hee
• Yamazaki, Osamu
• Ohana, Ehud
• Kurtz, Ira
• Shin, Dong Min
• Muallem, Shmuel

Titel

Intracellular Cl⁻ as a signaling ion that potently regulates Na⁺/HCO3⁻ transporters

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2015-01, Vol.112 (3), p.E329-E337

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Cl⁻ is a major anion in mammalian cells involved in transport processes that determines the intracellular activity of many ions and plasma membrane potential. Surprisingly, a role of intracellular Cl⁻ (Cl⁻in) as a signaling ion has not been previously evaluated. Here we report that Cl⁻infunctions as a regulator of cellular Na⁺ and HCO₃⁻ concentrations and transepithelial transport through modulating the activity of several electrogenic Na⁺-HCO₃⁻ transporters. We describe the molecular mechanism(s) of this regulation by physiological Cl⁻inconcentrations highlighting the role of GXXXP motifs in Cl⁻ sensing. Regulation of the ubiquitous Na⁺-HCO3⁻ cotransport (NBC)e1-B is mediated by two GXXXP-containing sites; regulation of NBCe2-C is dependent on a single GXXXP motif; and regulation of NBCe1-A depends on a cryptic GXXXP motif. In the basal state NBCe1-B is inhibited by high Cl⁻ininteracting at a low affinity GXXXP-containing site. IP₃ receptor binding protein released with IP₃ (IRBIT) activation of NBCe1-B unmasks a second high affinity Cl⁻ininteracting GXXXP-dependent site. By contrast, NBCe2-C, which does not interact with IRBIT, has a single high affinity N-terminal GXXP-containing Cl⁻ininteracting site. NBCe1-A is unaffected by Cl⁻inbetween 5 and 140 mM. However, deletion of NBCe1-A residues 29–41 unmasks a cryptic GXXXP-containing site homologous with the NBCe1-B low affinity site that is involved in inhibition of NBCe1-A by Cl⁻in. These findings reveal a cellular Cl⁻insensing mechanism that plays an important role in the regulation of Na⁺ and HCO₃⁻ transport, with critical implications for the role of Cl⁻ in cellular ion homeostasis and epithelial fluid and electrolyte secretion.