In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 3 ( 2015-01-20)
Abstract:
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 − in functions as a regulator of cellular Na + and HCO 3 − concentrations and transepithelial transport through modulating the activity of several electrogenic Na + -HCO 3 − transporters. We describe the molecular mechanism(s) of this regulation by physiological Cl − in concentrations highlighting the role of GXXXP motifs in Cl − sensing. Regulation of the ubiquitous Na + -HCO3 − co-transport (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 − in interacting at a low affinity GXXXP-containing site. IP 3 receptor binding protein released with IP 3 (IRBIT) activation of NBCe1-B unmasks a second high affinity Cl − in interacting GXXXP-dependent site. By contrast, NBCe2-C, which does not interact with IRBIT, has a single high affinity N-terminal GXXP-containing Cl − in interacting site. NBCe1-A is unaffected by Cl − in between 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 − in sensing mechanism that plays an important role in the regulation of Na + and HCO 3 − transport, with critical implications for the role of Cl − in cellular ion homeostasis and epithelial fluid and electrolyte secretion.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1415673112
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2015
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
