Nicotinic acid-adenine dinucleotide phosphate-sensitive calcium stores initiate insulin signaling in human beta cells

Abstract

Recent studies suggest a role for autocrine insulin signaling in beta cells, but the mechanism and function of insulin-stimulated Ca 2؉ signals is uncharacterized. We examined Ca 2؉ -dependent insulin signaling in human beta cells. calcium signals ͉ ryanodine ͉ autocrine ͉ CD38 ͉ diabetes mellitus D iscovery of insulin receptors on pancreatic beta cells and the characterization of beta cell-specific insulin receptor null mice with a diabetes-like phenotype suggest a physiological role for autocrine insulin signaling (1). Although results from in vivo and whole islet experiments suggested a negligible or inhibitory effect of insulin on insulin release, recent experiments with dispersed rodent beta cells suggested a stimulatory effect on calcium signaling, insulin expression, and exocytosis (2-7). Unlike glucose signaling, insulin-evoked Ca 2ϩ signals in mouse beta cells required intracellular Ca 2ϩ stores sensitive to the sarcoplasmic͞endoplasmic Ca 2ϩ -ATPase (SERCA) inhibitor thapsigargin (4). Insulin action was not blocked by a phospholipase C inhibitor, suggesting indirectly that inositol 1,4,5-trisphosphate (IP 3 )-sensitive Ca 2ϩ stores were not involved (5). The mechanisms of autocrine insulin feedback are unknown in human beta cells.Ca 2ϩ signals control multiple functions in secretory cells, and at least three distinct biochemical classes of Ca 2ϩ stores coexist (8, 9). Aside from the phospholipase C͞IP 3 pathway that is commonly activated by G-protein-coupled receptors, Ca 2ϩ can be mobilized through ryanodine receptors, activated by Ca 2ϩ or cyclic ADP-ribose (cADPr). A third class of Ca 2ϩ store, mobilized by nicotinic acid adenine dinucleotide phosphate (NAADP), functions in oocytes, Jurkat T lymphocytes, and mouse pancreatic acini (8, 10, 11). The production of NAADP and cADPr are catalyzed by CD38 and related ADP-ribosyl cyclases (12, 13). CD38 is found in many cell types, including human beta cells. Glucose-stimulated Ca 2ϩ mobilization and insulin release (in vivo and in vitro) were enhanced by CD38 overexpression and reduced by CD38 knockout (14,15). Beta cells with poor glucose-stimulated insulin production͞release (ob͞ob, GK, RINm5F) have less CD38 (16,17). CD38 autoantibodies, found in Ϸ14% of diabetic patients, evoked Ca 2ϩ signals and insulin release from human islet cells (18).In this study, we tested the hypothesis that NAADP-sensitive Ca 2ϩ stores regulate beta cell function, in the context of autocrine insulin signaling. We report that insulin generates complex Ca 2ϩ signals by mobilizing novel intracellular Ca 2ϩ stores in primary cultures of dispersed human islet cells. NAADPsensitive Ca 2ϩ stores initiate insulin signaling, whereas subsequent oscillatory behavior is sensitive to the removal of extracellular Ca 2ϩ and to putative IP 3 receptor inhibitors. These prolonged insulin-stimulated Ca 2ϩ signals regulate cellular insulin levels, but do not measurably stimulate overall secretion. Materials and MethodsDrugs and Solutions. Reagents were from Sigma unless otherwise stated. Stocks ...

Synergistic regulation of endogenous TRPM2 channels by adenine dinucleotides in primary human neutrophils

“…4B and D). This behavior may be due to the bell-shaped dose-response curve for NAADP-induced Ca 2+ -release observed in other cell systems [30][31][32], where optimal Ca 2+ -release is elicited by NAADP concentrations between 10 nM and 1 μM, but concentrations above 100 μM NAADP abolish Ca 2+ release. Thus, lower NAADP concentrations may cause additional Ca 2+ -release, which in conjunction with subthreshold ADPR facilitates TRPM2 currents in a narrow concentration window.…”

“…Thus, lower NAADP concentrations may cause additional Ca 2+ -release, which in conjunction with subthreshold ADPR facilitates TRPM2 currents in a narrow concentration window. This facilitatory action mediated by Ca 2+ would then be lost at higher NAADP concentrations even in the presence of subthreshold ADPR ( [30][31][32] and Fig. 4D).…”

Oscillatory control of insulin secretion

“…Insulin is believed to exert its acute stimulatory effect via Ca 2+ mobilized from intracellular stores (Xu et al, 1999;Aspinwall et al, 2000;Xu et al, 2000). The underlying mechanism is not clear, but may involve IRS-1-mediated SERCA inhibition (Xu et al, 1999;Xu et al, 2000;Borge and Wolf, 2003) or generation of the Ca 2+ mobilizing messenger nicotinic acid adenine dinucleotide phosphate (Johnson and Misler, 2002).…”

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

“…The primary effects of neurotransmitters and hormones on -cells often involve formation of inositol 1,4,5-trisphosphate (IP 3 ), which mobilizes Ca 2+ from the endoplasmic reticulum (ER) [2][3][4]. Cyclic ADP ribose (cADPr) [5] and nicotinic acid adenine dinucleotide phosphate (NAADP) [6,7] acting on separate receptors have also been suggested to mediate intracellular Ca 2+ mobilization in -cells. Although these pathways for elevation of [Ca 2+ ] i represent different processes there may be considerable interaction between them.…”

“…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].…”