Targeted expression of the inositol 1,4,5-triphosphate receptor (IP 3R) ligand-binding domain releases Ca2+ via endogenous IP3R channels

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36 Citations (Scopus)

Abstract

Virtually all functions of a cell are influenced by cytoplasmic [Ca 2+] increases. Inositol 1,4,5-trisphosphate receptor (IP 3R) channels, located in the endoplasmic reticulum (ER), release Ca2+ in response to binding of the second messenger, IP3. IP3Rs thus are part of the information chain interpreting external signals and transforming them into cytoplasmic Ca2+ transients. IP3Rs function as tetramers, each unit comprising an N-terminal ligand-binding domain (LBD) and a C-terminal channel domain linked by a long regulatory region. It is not yet understood how the binding of IP3 to the LBD regulates the gating properties of the channel. Here, we use the expression of IP3 binding protein domains tethered to the surface of the endoplasmic reticulum (ER) to show that the all-helical domain of the IP3R LBD is capable of depleting the ER Ca2+ pools by opening the endogenous IP3Rs, even without IP3 binding. This effect requires the domain to be within 50 Å of the ER membrane and is impaired by the presence of the N-terminal inhibitory segment on the LBD. These findings raise the possibility that the helical domain of the LBD functions as an effector module possibly interacting with the channel domain, thereby being part of the gating mechanisms by which the IP3-induced conformational change within the LBD regulates Ca2+ release.

Original languageEnglish
Pages (from-to)7859-7864
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number22
DOIs
Publication statusPublished - May 31 2005

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Inositol 1,4,5-Trisphosphate Receptors
Ligands
Endoplasmic Reticulum
Nucleic Acid Regulatory Sequences
Second Messenger Systems
Carrier Proteins
Membranes

Keywords

  • Ca channel
  • Endoplasmic reticulum
  • Red fluorescent protein

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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title = "Targeted expression of the inositol 1,4,5-triphosphate receptor (IP 3R) ligand-binding domain releases Ca2+ via endogenous IP3R channels",
abstract = "Virtually all functions of a cell are influenced by cytoplasmic [Ca 2+] increases. Inositol 1,4,5-trisphosphate receptor (IP 3R) channels, located in the endoplasmic reticulum (ER), release Ca2+ in response to binding of the second messenger, IP3. IP3Rs thus are part of the information chain interpreting external signals and transforming them into cytoplasmic Ca2+ transients. IP3Rs function as tetramers, each unit comprising an N-terminal ligand-binding domain (LBD) and a C-terminal channel domain linked by a long regulatory region. It is not yet understood how the binding of IP3 to the LBD regulates the gating properties of the channel. Here, we use the expression of IP3 binding protein domains tethered to the surface of the endoplasmic reticulum (ER) to show that the all-helical domain of the IP3R LBD is capable of depleting the ER Ca2+ pools by opening the endogenous IP3Rs, even without IP3 binding. This effect requires the domain to be within 50 {\AA} of the ER membrane and is impaired by the presence of the N-terminal inhibitory segment on the LBD. These findings raise the possibility that the helical domain of the LBD functions as an effector module possibly interacting with the channel domain, thereby being part of the gating mechanisms by which the IP3-induced conformational change within the LBD regulates Ca2+ release.",
keywords = "Ca channel, Endoplasmic reticulum, Red fluorescent protein",
author = "P. V{\'a}rnai and A. Balla and L. Hunyady and Tamas Balla",
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T1 - Targeted expression of the inositol 1,4,5-triphosphate receptor (IP 3R) ligand-binding domain releases Ca2+ via endogenous IP3R channels

AU - Várnai, P.

AU - Balla, A.

AU - Hunyady, L.

AU - Balla, Tamas

PY - 2005/5/31

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N2 - Virtually all functions of a cell are influenced by cytoplasmic [Ca 2+] increases. Inositol 1,4,5-trisphosphate receptor (IP 3R) channels, located in the endoplasmic reticulum (ER), release Ca2+ in response to binding of the second messenger, IP3. IP3Rs thus are part of the information chain interpreting external signals and transforming them into cytoplasmic Ca2+ transients. IP3Rs function as tetramers, each unit comprising an N-terminal ligand-binding domain (LBD) and a C-terminal channel domain linked by a long regulatory region. It is not yet understood how the binding of IP3 to the LBD regulates the gating properties of the channel. Here, we use the expression of IP3 binding protein domains tethered to the surface of the endoplasmic reticulum (ER) to show that the all-helical domain of the IP3R LBD is capable of depleting the ER Ca2+ pools by opening the endogenous IP3Rs, even without IP3 binding. This effect requires the domain to be within 50 Å of the ER membrane and is impaired by the presence of the N-terminal inhibitory segment on the LBD. These findings raise the possibility that the helical domain of the LBD functions as an effector module possibly interacting with the channel domain, thereby being part of the gating mechanisms by which the IP3-induced conformational change within the LBD regulates Ca2+ release.

AB - Virtually all functions of a cell are influenced by cytoplasmic [Ca 2+] increases. Inositol 1,4,5-trisphosphate receptor (IP 3R) channels, located in the endoplasmic reticulum (ER), release Ca2+ in response to binding of the second messenger, IP3. IP3Rs thus are part of the information chain interpreting external signals and transforming them into cytoplasmic Ca2+ transients. IP3Rs function as tetramers, each unit comprising an N-terminal ligand-binding domain (LBD) and a C-terminal channel domain linked by a long regulatory region. It is not yet understood how the binding of IP3 to the LBD regulates the gating properties of the channel. Here, we use the expression of IP3 binding protein domains tethered to the surface of the endoplasmic reticulum (ER) to show that the all-helical domain of the IP3R LBD is capable of depleting the ER Ca2+ pools by opening the endogenous IP3Rs, even without IP3 binding. This effect requires the domain to be within 50 Å of the ER membrane and is impaired by the presence of the N-terminal inhibitory segment on the LBD. These findings raise the possibility that the helical domain of the LBD functions as an effector module possibly interacting with the channel domain, thereby being part of the gating mechanisms by which the IP3-induced conformational change within the LBD regulates Ca2+ release.

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