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 + -HCO 3 - 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 - 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.
| Original language | English |
|---|---|
| Pages (from-to) | E329-E337 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 112 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2015 Jan 20 |
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Intracellular Cl-as a signaling ion that potently regulates Na+/Hco3 - Transporters. / Shcheynikov, Nikolay; Son, Aran; Hong, Jeong Hee; Yamazaki, Osamu; Ohana, Ehud; Kurtz, Ira; Shin, Dong Min; Muallem, Shmuel.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 3, 20.01.2015, p. E329-E337.Research output: Contribution to journal › Article
TY - JOUR
T1 - Intracellular Cl-as a signaling ion that potently regulates Na+/Hco3 - Transporters
AU - Shcheynikov, Nikolay
AU - Son, Aran
AU - Hong, Jeong Hee
AU - Yamazaki, Osamu
AU - Ohana, Ehud
AU - Kurtz, Ira
AU - Shin, Dong Min
AU - Muallem, Shmuel
PY - 2015/1/20
Y1 - 2015/1/20
N2 - 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 + -HCO 3 - 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 - 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.
AB - 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 + -HCO 3 - 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 - 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.
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U2 - 10.1073/pnas.1415673112
DO - 10.1073/pnas.1415673112
M3 - Article
C2 - 25561556
AN - SCOPUS:84922283734
VL - 112
SP - E329-E337
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 3
ER -