Crosstalk between the cAMP and Inositol Trisphosphate-Signalling Pathways in Pancreatic β-Cells

Oscillatory control of insulin secretion

“…Real-time imaging studies in isolated insulinoma cells and intact islets (Thore et al, 2004;Tamarina et al, 2005;Thore et al, 2007) have recently confirmed that glucose stimulates PLC activity secondary to the elevation of [Ca 2+ ] i and that membrane depolarization alone (Gromada et al, 1996;Liu et al, 1996) or increase of [Ca 2+ ] i (Mathias et al, 1985;Best et al, 1987;Biden et al, 1987) In addition to contributing to the generation and shaping of Ca 2+ signals, PLC activation can be anticipated to regulate insulin secretion kinetics via generation of DAG and activation of PKC. Several conventional, novel and atypical PKC isoforms are expressed in islets and insulin-secreting cells (Jones and Persaud, 1998;Warwar et al, 2006).…”

“…Although intracellular sequestration and release of Ca 2+ from the ER does not seem to be an absolute requirement for generating slow [Ca 2+ ] i oscillations (Liu et al, 1996), these processes contribute to shaping the oscillations (Fridlyand et al, 2003). SERCA inhibition (Gilon et al, 1999) (Table 1).…”

“…Such release can be triggered after activation of phosphoinositide-specific phospholipase C (PLC) by G-protein coupled hormone receptors (Grapengiesser et al, 1989a). Also elevation of cAMP promotes irregular Ca 2+ spiking that is superimposed on top of the slow oscillations or on a stably elevated [Ca 2+ ] i level Liu et al, 1996;Dyachok and Gylfe, 2004), reflecting facilitation of Ca 2+ -induced Ca 2+ release (CICR) via IP 3 Rs (Dyachok and Gylfe, 2004). Ca 2+ spiking is sufficiently pronounced to activate a hyperpolarizing K + current that can arrest action potential firing (Ämmälä et al, 1993b;Dryselius et al, 1999) and provide a negative feedback on the slow [Ca 2+ ] i oscillations (Bertram et al, 2007a;Bertram et al, 2007b) independent of the Ca 2+ effects on metabolism discussed above ( Figure 2D).…”

“…The effect of cAMP on Ca 2+ signals involves stimulation of both voltage-dependent Ca 2+ entry and intracellular mobilization of the ion from the ER Grapengiesser et al, 1989a;Liu et al, 1996). While the former effect can be explained by PKA phosphorylation of voltage-dependent Ca 2+ channels (Ämmälä et al, 1993a;Kanno et al, 1998) and K ATP channels (Holz et al, 1993;Gromada et al, 2004), the intracellular mobilization is most likely due to PKA phosphorylation and sensitization of IP 3 receptors (Liu et al, 1996;Dyachok and Gylfe, 2004).…”

Ca2+-induced Ca2+ release by activation of inositol 1,4,5-trisphosphate receptors in primary pancreatic β-cells

“…Emptying of the ER may consequently contribute to voltage-dependent influx of Ca 2+ by activation of a store-operated depolarizing current [8]. Glucose stimulation and the associated depolarization has been proposed to result in increased production of IP 3 [9][10][11], cADPr [5] and NAADP [6]. Another important mechanism is the Ca 2+ -induced Ca 2+ release (CICR), by which a depolarizationdependent rise of [Ca 2+ ] i may become amplified by Ca 2+ release from the ER [12].…”