Intracellular Cl-as a signaling ion that potently regulates Na+/Hco3 - Transporters

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 languageEnglish
Pages (from-to)E329-E337
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number3
DOIs
Publication statusPublished - 2015 Jan 20

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Ions
Fluids and Secretions
Membrane Potentials
Electrolytes
Anions
Carrier Proteins
Homeostasis
Cell Membrane

All Science Journal Classification (ASJC) codes

  • General

Cite this

Shcheynikov, Nikolay ; Son, Aran ; Hong, Jeong Hee ; Yamazaki, Osamu ; Ohana, Ehud ; Kurtz, Ira ; Shin, DongMin ; Muallem, Shmuel. / Intracellular Cl-as a signaling ion that potently regulates Na+/Hco3 - Transporters. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 3. pp. E329-E337.
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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.",
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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, DongMin; 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 journalArticle

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, DongMin

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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