Dataset Information

IP₃ receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer.

ABSTRACT: Contact sites of endoplasmic reticulum (ER) and mitochondria locally convey calcium signals between the IP₃ receptors (IP3R) and the mitochondrial calcium uniporter, and are central to cell survival. It remains unclear whether IP3Rs also have a structural role in contact formation and whether the different IP3R isoforms have redundant functions. Using an IP3R-deficient cell model rescued with each of the three IP3R isoforms and an array of super-resolution and ultrastructural approaches we demonstrate that IP3Rs are required for maintaining ER-mitochondrial contacts. This role is independent of calcium fluxes. We also show that, while each isoform can support contacts, type 2 IP3R is the most effective in delivering calcium to the mitochondria. Thus, these studies reveal a non-canonical, structural role for the IP3Rs and direct attention towards the type 2 IP3R that was previously neglected in the context of ER-mitochondrial calcium signaling.

SUBMITTER: Bartok A

PROVIDER: S-EPMC6700175 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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IP<sub>3</sub> receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer.

Bartok Adam A Weaver David D Golenár Tünde T Nichtova Zuzana Z Katona Máté M Bánsághi Száva S Alzayady Kamil J KJ Thomas V Kaye VK Ando Hideaki H Mikoshiba Katsuhiko K Joseph Suresh K SK Yule David I DI Csordás György G Hajnóczky György G

Nature communications 20190819 1

Contact sites of endoplasmic reticulum (ER) and mitochondria locally convey calcium signals between the IP<sub>3</sub> receptors (IP3R) and the mitochondrial calcium uniporter, and are central to cell survival. It remains unclear whether IP3Rs also have a structural role in contact formation and whether the different IP3R isoforms have redundant functions. Using an IP3R-deficient cell model rescued with each of the three IP3R isoforms and an array of super-resolution and ultrastructural approach ...[more]

PMID: 31427578

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Project description:Intracellular Ca2+ is critical for regulating airway smooth muscle (ASM) tension. A rapid rise in the intracellular Ca2+ concentration ([Ca2+]i) of ASM cells is crucial for modulating the intensity and length of the ASM contraction. Because this rapid increase in [Ca2+]i largely depends on the balance between Ca2+ released from intracellular Ca2+ stores and extracellular Ca2+ entry, exploring the mechanisms mediating Ca2+ transport is critical for understanding ASM contractility and the pathogenesis of bronchial contraction disorders. Transient receptor potential vanilloid 4 (TRPV4) is a highly Ca2+-permeable non-selective cation channel that mediates Ca2+ influx to increase [Ca2+]i, which then directly or indirectly regulates the contraction and relaxation of ASM. The [Ca2+]i returns to basal levels through several uptake and extrusion pumps, such as the sarco(endo)plasmic reticulum Ca2+ ATPase and inositol 1,4,5-trisphosphate receptors (IP3Rs), the plasmalemmal Ca2+ ATPase, and the plasma membrane Na+/Ca2+ exchanger (NCX). Thus, to further understand ASM tension regulation in normal and diseased tissue, the present study examined whether an interaction exists among TRPV4, IP3Rs, and NCX. The TRPV4-specific and potent agonist GSK1016790A increased [Ca2+]i in mouse ASM cells, an effect that was completely blocked by the TRPV4-specific antagonist HC067047. However, GSK1016790A induced relaxation in mouse tracheal rings precontracted with carbachol in vitro. To determine the mechanism underlying this TRPV4-induced relaxation of ASM, we blocked specific downstream molecules. We found that the GSK1016790A-induced relaxation was abolished by the NCX inhibitors KB-R7943 and LiCl but not by specific inhibitors of the Ca2+-activated large-, intermediate-, or small-conductance K+ channels (BKCa, IK, and SK3, respectively). The results of co-immunoprecipitation (co-IP) assays showed an interaction of TRPV4 and IP3R1 with NCXs. Taken together, these findings support a physical and functional interaction of TRPV4 and IP3R1 with NCXs as a novel TRPV4-mediated Ca2+ signaling mechanism and suggest a potential target for regulation of ASM tension and treatment of respiratory diseases, especially tracheal spasm.

Dataset Information

IP₃ receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer.

Publications

IP<sub>3</sub> receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer.

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Dataset Information

IP3 receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer.

Publications

IP<sub>3</sub> receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

IP₃ receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer.