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"Powell, Trevor"
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Glucose and NAADP trigger elementary intracellular β-cell Ca2+ signals
Pancreatic β-cells release insulin upon a rise in blood glucose. The precise mechanisms of stimulus-secretion coupling, and its failure in Diabetes Mellitus Type 2, remain to be elucidated. The consensus model, as well as a class of currently prescribed anti-diabetic drugs, are based around the observation that glucose-evoked ATP production in β-cells leads to closure of cell membrane ATP-gated potassium (K
ATP
) channels, plasma membrane depolarisation, Ca
2+
influx, and finally the exocytosis of insulin granules. However, it has been demonstrated by the inactivation of this pathway using genetic and pharmacological means that closure of the K
ATP
channel alone may not be sufficient to explain all β-cell responses to glucose elevation. We have previously proposed that NAADP-evoked Ca
2+
release is an important step in stimulus-secretion coupling in pancreatic β-cells. Here we show using total internal reflection fluorescence (TIRF) microscopy that glucose as well as the Ca
2+
mobilising messenger nicotinic acid adenine dinucleotide phosphate (NAADP), known to operate in β-cells, lead to highly localised elementary intracellular Ca
2+
signals. These were found to be obscured by measurements of global Ca
2+
signals and the action of powerful SERCA-based sequestration mechanisms at the endoplasmic reticulum (ER). Building on our previous work demonstrating that NAADP-evoked Ca
2+
release is an important step in stimulus-secretion coupling in pancreatic β-cells, we provide here the first demonstration of elementary Ca
2+
signals in response to NAADP, whose occurrence was previously suspected. Optical quantal analysis of these events reveals a unitary event amplitude equivalent to that of known elementary Ca
2+
signalling events, inositol trisphosphate (IP
3
) receptor mediated blips, and ryanodine receptor mediated quarks. We propose that a mechanism based on these highly localised intracellular Ca
2+
signalling events mediated by NAADP may initially operate in β-cells when they respond to elevations in blood glucose.
Journal Article
Precipitation of Sulfide Ores and Organic Matter: Sulfate Reactions at Pine Point, Canada
Bitumen is a common associate of carbonate-hosted lead-zinc deposits. On the Pine Point lead-zinc property, Northwest Territories, Canada, there are two forms of bitumen. Unaltered bitumens have atomic hydrogen/carbon ratios of about 1.4, sulfur contents of about 7.8 percent, and sulfur isotope ratios ($\\delta ^{34}$S) of approximately +4.6 per mil. Altered bitumens occur in proximity to sulfide ore bodies and white sparry dolomite. Their hydrogen/carbon ratios are about 1.02, the sulfur contents average 22 percent, and the $\\delta ^{34}$S values are about +12.4 per mil. These data indicate that some bitumen has participated in the thermochemical reduction of sulfate to produce hydrogen sulfide required to precipitate the ores. Mass balance considerations show that the amount and degree of alteration of bitumen is more than adequate to account for the reduced sulfur species (lead, zinc, and iron sulfides) deposited at Pine Point. These reactions may provide an important means of generating the large volumes of sulfide necessary to precipitate ore bodies in carbonate rocks.
Journal Article
Glucose and NAADP trigger elementary intracellular β-cell Ca2+ signals
Abstract Pancreatic β-cells release insulin upon a rise in blood glucose. The precise mechanisms of stimulus-secretion coupling, and its failure in Diabetes Mellitus Type 2, remain to be elucidated. The consensus model, as well as a class of currently prescribed anti-diabetic drugs, are based around the observation that glucose-evoked ATP production in β-cells leads to closure of cell membrane ATP-gated potassium (KATP) channels, plasma membrane depolarisation, Ca2+ influx, and finally the exocytosis of insulin granules (Ashcroft et al., 1984; Cook and Hales, 1984). However, it has been demonstrated by the inactivation of this pathway using genetic and pharmacological means that closure of the KATP channel alone may not be sufficient to explain all β-cell responses to glucose elevation (Henquin, 1998; Seghers et al., 2000). Here we show using total internal reflection fluorescence (TIRF) microscopy (Axelrod, 1981) that glucose as well as the Ca2+ mobilising messenger nicotinic acid adenine dinucleotide phosphate (NAADP), known to operate in β-cells (Johnson and Misler, 2002; Masgrau et al., 2003), lead to highly localised elementary intracellular Ca2+ signals. These were found to be obscured by measurements of global Ca2+ signals and the action of powerful SERCA-based sequestration mechanisms at the endoplasmic reticulum (ER). This is the first demonstration of elemental Ca2+ signals in response to NAADP, although they have been suspected (Davis et al., 2020). Optical quantal analysis of these events reveals a unitary event amplitude equivalent to that of known elementary Ca2+ signalling events, inositol trisphosphate (IP3) receptor mediated blips (Parker et al., 1996; Parker and Ivorra, 1990), and ryanodine receptor mediated sparks (Cheng et al., 1993). We propose that a mechanism based on these highly localised intracellular Ca2+ signalling events mediated by NAADP may initially operate in β-cells when they respond to elevations in blood glucose. Competing Interest Statement The authors have declared no competing interest.
Paper
To Burwash, with origami
Powell is the headteacher at Burwash--a village Church of England primary in East Sussex. He comments on the rewarding experience of hosting Masako Mikami for two terms. Mikami is a 21-year-old English literature graduate from Japan.
Trade Publication Article