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Acetylcholine promotes Ca2+ and NO-oscillations in adipocytes implicating Ca2+?NO?cGMP?cADP-ribose?Ca2+ positive feedback loop--modulatory effects of norepinephrine and atrial natriuretic peptide.

ABSTRACT:

Purpose

This study investigated possible mechanisms of autoregulation of Ca(2+) signalling pathways in adipocytes responsible for Ca(2+) and NO oscillations and switching phenomena promoted by acetylcholine (ACh), norepinephrine (NE) and atrial natriuretic peptide (ANP).

Methods

Fluorescent microscopy was used to detect changes in Ca(2+) and NO in cultures of rodent white adipocytes. Agonists and inhibitors were applied to characterize the involvement of various enzymes and Ca(2+)-channels in Ca(2+) signalling pathways.

Results

ACh activating M3-muscarinic receptors and G?? protein dependent phosphatidylinositol 3 kinase induces Ca(2+) and NO oscillations in adipocytes. At low concentrations of ACh which are insufficient to induce oscillations, NE or ?1, ?2-adrenergic agonists act by amplifying the effect of ACh to promote Ca(2+) oscillations or switching phenomena. SNAP, 8-Br-cAMP, NAD and ANP may also produce similar set of dynamic regimes. These regimes arise from activation of the ryanodine receptor (RyR) with the implication of a long positive feedback loop (PFL): Ca(2+)?NO?cGMP?cADPR?Ca(2+), which determines periodic or steady operation of a short PFL based on Ca(2+)-induced Ca(2+) release via RyR by generating cADPR, a coagonist of Ca(2+) at the RyR. Interplay between these two loops may be responsible for the observed effects. Several other PFLs, based on activation of endothelial nitric oxide synthase or of protein kinase B by Ca(2+)-dependent kinases, may reinforce functioning of main PFL and enhance reliability. All observed regimes are independent of operation of the phospholipase C/Ca(2+)-signalling axis, which may be switched off due to negative feedback arising from phosphorylation of the inositol-3-phosphate receptor by protein kinase G.

Conclusions

This study presents a kinetic model of Ca(2+)-signalling system operating in adipocytes and integrating signals from various agonists, which describes it as multivariable multi feedback network with a family of nested positive feedback.

SUBMITTER: Turovsky EA

PROVIDER: S-EPMC3656004 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Acetylcholine promotes Ca2+ and NO-oscillations in adipocytes implicating Ca2+→NO→cGMP→cADP-ribose→Ca2+ positive feedback loop--modulatory effects of norepinephrine and atrial natriuretic peptide.

Turovsky Egor A EA Turovskaya Mariya V MV Dolgacheva Ludmila P LP Zinchenko Valery P VP Dynnik Vladimir V VV

PloS one 20130516 5

<h4>Purpose</h4>This study investigated possible mechanisms of autoregulation of Ca(2+) signalling pathways in adipocytes responsible for Ca(2+) and NO oscillations and switching phenomena promoted by acetylcholine (ACh), norepinephrine (NE) and atrial natriuretic peptide (ANP).<h4>Methods</h4>Fluorescent microscopy was used to detect changes in Ca(2+) and NO in cultures of rodent white adipocytes. Agonists and inhibitors were applied to characterize the involvement of various enzymes and Ca(2+) ...[more]

PMID: 23696827

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