Dual effect of nitric oxide on cytosolic Ca²⁺concentration and insulin secretion in rat pancreatic β-cells

Abstract

Kaneko, Yukiko, Tomohisa Ishikawa, Satoshi Amano, and Koichi Nakayama. Dual effect of nitric oxide on cytosolic Ca 2ϩ concentration and insulin secretion in rat pancreatic ␤-cells. Am J Physiol Cell Physiol 284: C1215-C1222, 2003. First published January 15, 2003 10.1152/ajpcell.00223.2002In isolated rat pancreatic ␤-cells, the nitric oxide (NO) donor NOC-7 at 1 M reduced the amplitude of the oscillations of cytosolic Ca 2ϩ concentration ([Ca 2ϩ ]c) induced by 11.1 mM glucose, and at 10 M terminated them. In the presence of N G -nitro-L-arginine (L-NNA), however, NOC-7 at 0.5 and 1 M increased the amplitude of the [Ca 2ϩ ]c oscillations, although the NO donor at 10 M still suppressed them. Aqueous NO solution also had a dual effect on the [Ca 2ϩ ]c oscillations. The soluble guanylate cyclase inhibitor LY-83583 and the cGMP-dependent protein kinase inhibitor KT5823 inhibited the stimulatory effect of NO, and 8-bromo-cGMP increased the amplitude of the [Ca 2ϩ ]c oscillations. Patch-clamp analyses in the perforated configuration showed that 8-bromo-cGMP inhibited whole cell ATP-sensitive K ϩ currents in the isolated rat pancreatic ␤-cells, suggesting that the inhibition by cGMP of ATP-sensitive K ϩ channels is, at least in part, responsible for the stimulatory effect of NO on the [Ca 2ϩ ]c oscillations. In the presence of L-NNA, the glucose-induced insulin secretion from isolated islets was facilitated by 0.5 M NOC-7, whereas it was suppressed by 10 M NOC-7. These results suggest that NO facilitates glucose-induced [Ca 2ϩ ]c oscillations of ␤-cells and insulin secretion at low concentrations, which effects are mediated by cGMP, whereas NO inhibits them in a cGMP-independent manner at high concentrations.islets of Langerhans; calcium oscillations; guanosine 3Ј,5Ј-cyclic monophosphate; NOC-7; glucose NITRIC OXIDE (NO) produced from L-arginine by NO synthase (NOS) is an important regulator of various physiological and pathological functions in various types of cells. In pancreatic islets, a large amount of NO generated by inducible NOS (iNOS) has been postulated to be involved in ␤-cell degeneration in the process of insulin-dependent diabetes mellitus (1,6,22). On the other hand, recent immunostaining studies clearly demonstrated the presence of constitutive NOS (cNOS), which is activated by Ca 2ϩ and calmodulin, in rat and mouse pancreatic islet cells, i.e., neuronal NOS in ␣-, ␤-, and ␦-cells (3, 25) and endothelial NOS in ␣-and ␦-cells (37). Furthermore, direct biochemical evidence for the cNOS enzyme activity was obtained from isolated islets of mice (33). These findings suggest a physiological involvement of NO in the regulation of the hormone secretion from pancreatic islet cells.By binding to iron in the heme at the active site of soluble guanylate cyclase (sGC), NO activates the enzyme, which results in elevation of the cGMP level. Given that the enzyme activities of guanylate cyclase (16) and cGMP-dependent protein kinase have been demonstrated in pancreatic islets (23), it is plausible that NO ...

Identification of Nitric Oxide as an Endogenous Activator of the AMP-activated Protein Kinase in Vascular Endothelial Cells

“…For example, Wohlfart et al (33) and Hwang et al (34) found that activation of guanylyl cyclase stimulated an NO synthesis and release in endothelial cells, which is independent of the elevation of cyclic GMP but strictly dependent on calcium. Consistently, 8-bromo-cGMP is also found to increase the amplitude of the Ca 2ϩ oscillations (35). Other studies (36,37) found that cGMP has two distinct effects on the Ca 2ϩ : a facilitation of the Ca 2ϩ influx through L-type voltage-operated Ca 2ϩ channels and an acceleration of the Ca 2ϩ sequestration in the endoplasmic reticulum.…”

Reactive oxygen and nitrogen species disturb Ca2+oscillations in insulin-secreting MIN6 β-cells

“…11 Similarly, reactive nitrogen species (RNS) have beneficial or detrimental effects on b-cell function depending on their levels. 12 In agreement with this tenet we show here that massive ROS/RNS production by photoactivation of AlClPc at maximal (100%) LED intensity abolished Ca 2C oscillations in MIN6 b-cells (Fig. 2), while moderate ROS/RNS production (10% LED) accelerated the periodic Ca 2C excursions (Fig.…”

“…10 Hence, ROS may act as a double-edged sword: moderate and short-term elevations play a positive signaling role augmenting insulin secretion, but prolonged exposure to elevated ROS levels, characteristic of oxidative stress, are detrimental for the b-cells. 9,11 Similarly, reactive nitrogen species (RNS), such as nitric oxide (NO), have been shown to elevate Ca 2C levels and stimulate insulin secretion at low concentrations, 12 whereas high NO concentrations exert an inhibitory effect on b-cell function 12 and survival. 13 ROS/RNS target various cellular mechanisms underlying insulin secretion, 9 and in particular components involved in Ca 2C handling.…”

Nitric oxide enhances collagen synthesis in cultured human tendon cells

“…It is likely that the timing and level of NO production in the healing wound must be carefully balanced to ensure a beneficial effect. [39][40][41][42] This work also demonstrated that human tendon cells have the capacity to synthesize physiologically active NO following transfection of iNOS gene via adenovirus.…”