Microdomains of muscarinic acetylcholine and InsP3 receptors create InsP3 junctions and sites of Ca2+ wave initiation in smooth muscle

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Abstract

Inositol 1,4,5-trisphosphate (InsP3)-mediated increases in cytosolic Ca2+ concentration ([Ca2+]c) regulate activities which include division, contraction and cell death. InsP3-evoked Ca2+ release often begins in a single site then regeneratively propagates through the cell as a Ca2+ wave. The Ca2+ wave consistently begins at the same site on successive activations. We addressed the mechanisms that determine the Ca2+ wave initiation site in intestinal smooth muscle cells. Neither an increased sensitivity of InsP3 receptors (InsP3R) to InsP3 nor regional clustering of muscarinic receptors (mAChR3) or InsP3R1 explained the initiation site. However, examination of the overlap of mAChR3 and InsP3R1 by centre of mass analysis revealed a small percentage (~10%) of sites which showed colocalisation. Indeed, the extent of colocalisation was greatest at Ca2+ wave initiation site. The initiation site may arise from a selective delivery of InsP3 from mAChR3 activity to particular InsP3R to generate faster local [Ca2+]c increases at sites of co-localization. In support, a localized subthreshold ‘priming’ InsP3 concentration applied rapidly but at regions distant from the initiation site shifted the wave to the site of priming InsP3 release. Conversely, when the Ca2+ rise at the initiation site was rapidly and selectively attenuated the Ca2+ wave again shifted and initiated at a new site. These results indicate that Ca2+ waves initiate where there is a structural and functional coupling of mAChR3 and InsP3R1 which generates junctions in which InsP3 acts as a highly localized signal by being rapidly and selectively delivered to InsP3R
LanguageEnglish
Pages5315-5328
Number of pages14
JournalJournal of Cell Science
Volume125
Early online date3 Sep 2012
DOIs
Publication statusPublished - 15 Nov 2012

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Inositol 1,4,5-Trisphosphate
Muscarinic Receptors
Smooth Muscle Myocytes
Smooth Muscle
Cluster Analysis
Cell Death

Keywords

  • microdomains
  • muscarinic acetylcholine
  • InsP3 receptors
  • InsP3 junctions
  • Ca2+ wave initiation
  • smooth muscle

Cite this

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title = "Microdomains of muscarinic acetylcholine and InsP3 receptors create InsP3 junctions and sites of Ca2+ wave initiation in smooth muscle",
abstract = "Inositol 1,4,5-trisphosphate (InsP3)-mediated increases in cytosolic Ca2+ concentration ([Ca2+]c) regulate activities which include division, contraction and cell death. InsP3-evoked Ca2+ release often begins in a single site then regeneratively propagates through the cell as a Ca2+ wave. The Ca2+ wave consistently begins at the same site on successive activations. We addressed the mechanisms that determine the Ca2+ wave initiation site in intestinal smooth muscle cells. Neither an increased sensitivity of InsP3 receptors (InsP3R) to InsP3 nor regional clustering of muscarinic receptors (mAChR3) or InsP3R1 explained the initiation site. However, examination of the overlap of mAChR3 and InsP3R1 by centre of mass analysis revealed a small percentage (~10{\%}) of sites which showed colocalisation. Indeed, the extent of colocalisation was greatest at Ca2+ wave initiation site. The initiation site may arise from a selective delivery of InsP3 from mAChR3 activity to particular InsP3R to generate faster local [Ca2+]c increases at sites of co-localization. In support, a localized subthreshold ‘priming’ InsP3 concentration applied rapidly but at regions distant from the initiation site shifted the wave to the site of priming InsP3 release. Conversely, when the Ca2+ rise at the initiation site was rapidly and selectively attenuated the Ca2+ wave again shifted and initiated at a new site. These results indicate that Ca2+ waves initiate where there is a structural and functional coupling of mAChR3 and InsP3R1 which generates junctions in which InsP3 acts as a highly localized signal by being rapidly and selectively delivered to InsP3R",
keywords = "microdomains, muscarinic acetylcholine, InsP3 receptors , InsP3 junctions , Ca2+ wave initiation , smooth muscle",
author = "Olson, {Marnie L.} and Sandison, {Mairi E.} and Susan Chalmers and McCarron, {John G.}",
year = "2012",
month = "11",
day = "15",
doi = "10.1242/​jcs.105163",
language = "English",
volume = "125",
pages = "5315--5328",
journal = "Journal of Cell Science",
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TY - JOUR

T1 - Microdomains of muscarinic acetylcholine and InsP3 receptors create InsP3 junctions and sites of Ca2+ wave initiation in smooth muscle

AU - Olson, Marnie L.

AU - Sandison, Mairi E.

AU - Chalmers, Susan

AU - McCarron, John G.

PY - 2012/11/15

Y1 - 2012/11/15

N2 - Inositol 1,4,5-trisphosphate (InsP3)-mediated increases in cytosolic Ca2+ concentration ([Ca2+]c) regulate activities which include division, contraction and cell death. InsP3-evoked Ca2+ release often begins in a single site then regeneratively propagates through the cell as a Ca2+ wave. The Ca2+ wave consistently begins at the same site on successive activations. We addressed the mechanisms that determine the Ca2+ wave initiation site in intestinal smooth muscle cells. Neither an increased sensitivity of InsP3 receptors (InsP3R) to InsP3 nor regional clustering of muscarinic receptors (mAChR3) or InsP3R1 explained the initiation site. However, examination of the overlap of mAChR3 and InsP3R1 by centre of mass analysis revealed a small percentage (~10%) of sites which showed colocalisation. Indeed, the extent of colocalisation was greatest at Ca2+ wave initiation site. The initiation site may arise from a selective delivery of InsP3 from mAChR3 activity to particular InsP3R to generate faster local [Ca2+]c increases at sites of co-localization. In support, a localized subthreshold ‘priming’ InsP3 concentration applied rapidly but at regions distant from the initiation site shifted the wave to the site of priming InsP3 release. Conversely, when the Ca2+ rise at the initiation site was rapidly and selectively attenuated the Ca2+ wave again shifted and initiated at a new site. These results indicate that Ca2+ waves initiate where there is a structural and functional coupling of mAChR3 and InsP3R1 which generates junctions in which InsP3 acts as a highly localized signal by being rapidly and selectively delivered to InsP3R

AB - Inositol 1,4,5-trisphosphate (InsP3)-mediated increases in cytosolic Ca2+ concentration ([Ca2+]c) regulate activities which include division, contraction and cell death. InsP3-evoked Ca2+ release often begins in a single site then regeneratively propagates through the cell as a Ca2+ wave. The Ca2+ wave consistently begins at the same site on successive activations. We addressed the mechanisms that determine the Ca2+ wave initiation site in intestinal smooth muscle cells. Neither an increased sensitivity of InsP3 receptors (InsP3R) to InsP3 nor regional clustering of muscarinic receptors (mAChR3) or InsP3R1 explained the initiation site. However, examination of the overlap of mAChR3 and InsP3R1 by centre of mass analysis revealed a small percentage (~10%) of sites which showed colocalisation. Indeed, the extent of colocalisation was greatest at Ca2+ wave initiation site. The initiation site may arise from a selective delivery of InsP3 from mAChR3 activity to particular InsP3R to generate faster local [Ca2+]c increases at sites of co-localization. In support, a localized subthreshold ‘priming’ InsP3 concentration applied rapidly but at regions distant from the initiation site shifted the wave to the site of priming InsP3 release. Conversely, when the Ca2+ rise at the initiation site was rapidly and selectively attenuated the Ca2+ wave again shifted and initiated at a new site. These results indicate that Ca2+ waves initiate where there is a structural and functional coupling of mAChR3 and InsP3R1 which generates junctions in which InsP3 acts as a highly localized signal by being rapidly and selectively delivered to InsP3R

KW - microdomains

KW - muscarinic acetylcholine

KW - InsP3 receptors

KW - InsP3 junctions

KW - Ca2+ wave initiation

KW - smooth muscle

UR - http://jcs.biologists.org/content/125/22/5315.abstract?sid=f03a465c-0be7-4be1-92c1-f9a1c1ca60da

U2 - 10.1242/​jcs.105163

DO - 10.1242/​jcs.105163

M3 - Article

VL - 125

SP - 5315

EP - 5328

JO - Journal of Cell Science

T2 - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

ER -