Abstract
PurposeThis study investigated possible mechanisms of autoregulation of Ca2+ signalling pathways in adipocytes responsible for Ca2+ and NO oscillations and switching phenomena promoted by acetylcholine (ACh), norepinephrine (NE) and atrial natriuretic peptide (ANP).MethodsFluorescent microscopy was used to detect changes in Ca2+ and NO in cultures of rodent white adipocytes. Agonists and inhibitors were applied to characterize the involvement of various enzymes and Ca2+-channels in Ca2+ signalling pathways.ResultsACh activating M3-muscarinic receptors and Gβγ protein dependent phosphatidylinositol 3 kinase induces Ca2+ 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 Ca2+ 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): Ca2+→ NO→cGMP→cADPR→Ca2+, which determines periodic or steady operation of a short PFL based on Ca2+-induced Ca2+ release via RyR by generating cADPR, a coagonist of Ca2+ 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 Ca2+-dependent kinases, may reinforce functioning of main PFL and enhance reliability. All observed regimes are independent of operation of the phospholipase C/Ca2+-signalling axis, which may be switched off due to negative feedback arising from phosphorylation of the inositol-3-phosphate receptor by protein kinase G.ConclusionsThis study presents a kinetic model of Ca2+-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.
Highlights
The parasympathetic nervous system plays an important role in the control of circulating glucose and insulin [1,2,3,4,5,6]
Direct vagal control of white adipose tissue (WAT) currently remains under debate [18,19,20,21,22], while the metabolic effects of ACh on glucose and lipid metabolism are not studied in details and some results are contradictory
Irrespective of Ca2+-oscillatory mechanisms, a very interesting kinetic model linking the NORcGMPRPKG and cADPRR RyRRCa2+ signalling pathways was offered some years later [78]. This model may be considered as a core mechanism of Ca2+ signalling via ryanodine receptor (RyR) in non-excitable cells. Taking all this into consideration, the main goal of this work is to show that ACh induces Ca2+ oscillations implicating both: Ca2+RNOR cGMPRcADPRRCa2+ long positive feedback loop (PFL) and a short PFL based on Ca2+ induced Ca2+ release (CICR) via RyR, with the possible involvement of other reinforcing PFLs
Summary
The parasympathetic nervous system plays an important role in the control of circulating glucose and insulin [1,2,3,4,5,6]. Stimulation of parasympathetic nerves results in: acceleration of insulin production by pancreatic b-cells [5,6,7], suppression of glucose production and augmentation of glucose uptake by liver [4]. Acetylcholine (ACh), the principal neurotransmitter of the parasympathetic nervous system, realizes its metabolic effects by activating M3cholinergic receptors (M3-AChR) in the pancreas [6,7,8], liver [9,10], skeletal [11] and smooth [12] muscles and white adipose tissue (WAT) [13,14]. Direct vagal (parasympathetic) control of WAT currently remains under debate [18,19,20,21,22], while the metabolic effects of ACh on glucose and lipid metabolism are not studied in details and some results are contradictory.
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