title: 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: OBJECTIVE
  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 Gβγ 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 α1, α2-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.
authors.affiliation: Department of Intracellular Signalling, Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia.
authors.forename: Egor A
authors.initials: EA
authors.lastname: Turovsky
authors.forename: Mariya V
authors.initials: MV
authors.lastname: Turovskaya
authors.forename: Ludmila P
authors.initials: LP
authors.lastname: Dolgacheva
authors.forename: Valery P
authors.initials: VP
authors.lastname: Zinchenko
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Dynnik
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D051379:Mice; D009589:Nitrogen Oxides / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009589:Nitrogen Oxides; D036563:Cyclic ADP-Ribose; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP; D000109:Acetylcholine; D002118:Calcium; D009638:Norepinephrine