Inositol (1,4,5)-Trisphosphate Dynamics and Intracellular Calcium Oscillations in Pancreatic β-Cells

Abstract

Glucose-stimulated insulin secretion is associated with transients of intracellular calcium concentration ([Ca2؉is an important signaling mechanism in the glucose-stimulated ␤-cell (10,11). ␤-Cells have been shown to contain inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ] receptors (12), ryanodine receptors (4,10), and Ca 2ϩ channels gated by cyclic ADP-ribose (13) or nicotinic acid adenine dinucleotide phosphate (14,15). Ins(1,4,5)P 3 -dependent mobilization of endoplasmic reticulum Ca 2ϩ has been well described in ␤-cells as part of the response to various agonists, such as acetylcholine, purine nucleotides, or histamines. However, it is still unclear whether Ins(1,4,5)P 3 signaling is important in glucose-dependent ␤-cell activation, particularly for [Ca 2ϩ ] i oscillations. Our simulations of ␤-cell calcium responses, taking into account ATP and Na ϩ homeostasis as well as uptake and release of Ca 2ϩ by the endoplasmic reticulum, indicate that Ca 2ϩ in the endoplasmic reticulum is one of the main variables driving [Ca 2ϩ ] i oscillations (16). Our model suggested that the effect of regulated Ca 2ϩ efflux from the intracellular stores could shape the pattern of slow calcium oscillations. Using a biosensor capable of reporting Ins(1,4,5)P 3 (17) and confocal microscopy, we have demonstrated dynamics of Ins(1,4,5)P 3 in mouse primary ␤-cells and in MIN6 insulinoma cells upon stimulation with glucose and carbamoylcholine (CCh), as well as depolarization with KCl. We show that Ins(1,4,5)P 3 concentration oscillates in parallel with [Ca 2ϩ ] i in response to glucose stimulation, but it is not the driving force for [Ca 2ϩ ] i oscillations. RESEARCH DESIGN AND METHODSIsolation and culturing of mouse islets of Langerhans and islet cells. Islets were isolated from the pancreata of 1-to 5-month-old C57BL/J6 mice (The Jackson Laboratories) as described previously (7

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).…”

Rapid Turnover of Phosphatidylinositol-4,5-Bisphosphate in Insulin-Secreting Cells Mediated by Ca2+ and the ATP-to-ADP Ratio

“…Whereas several studies indicate that the glucoseinduced phosphoinositide hydrolysis depends on the presence of extracellular Ca 2ϩ (9,11,12), other reports indicate that the process is at least in part Ca 2ϩ independent (13)(14)(15). Recent observations in single insulinoma cells (16) and intact mouse islets (17) have demonstrated that elevation of [Ca 2ϩ ] i is sufficient to trigger PLC activity and that [Ca 2ϩ ] i oscillations are associated with periodic activation of PLC. However, the kinetics of the early changes in PIP 2 concentration and how it is related to [Ca 2ϩ ] i after glucose stimulation are unknown.…”

Modulation of the Pancreatic Islet β-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate

“…The extent of ␤-cell depolarization and insulin release are regulated in part by the activation of repolarizing ion channels, including the voltage-gated potassium channel, Kv2.1 (2)(3)(4). One mechanism employed by pancreatic ␤-cells to regulate the biophysical activity of the ion channels involved in insulin release involves hydrolysis of membrane phospholipids to yield mediators that include inositol triphosphates and free fatty acids (5)(6)(7)(8).…”

“…Pharmacologic, biochemical, and genetic evidence suggests that glucose-stimulated hydrolysis of esterified arachidonic acid from ␤-cell membrane phospholipids is required for physiological insulin secretion (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Pancreatic islet ␤-cells contain high levels of arachidonic acid compared with other tissues (7, 9 -12 24, 25), and about two-thirds of islet ␤-cell glycerophospholipids contain arachidonic acid as the sn-2 substituent (23)(24)(25).…”