ATP-Sensitive K+ Channel–Dependent Regulation of Glucagon Release and Electrical Activity by Glucose in Wild-Type and SUR1−/− Mouse α-Cells

Gromada, Jesper; Ma, Xiaosong; Høy, Marianne; Bokvist, Krister; Salehi, Albert; Berggren, Per Olof; Rorsman, Patrik

doi:10.2337/diabetes.53.suppl_3.s181

Cited by 153 publications

(200 citation statements)

References 48 publications

Supporting

Mentioning

182

Contrasting

Unclassified

Order By: Relevance

“…Activation of alpha cell voltage-gated Ca 2+ channels and the resultant glucagon secretion requires the activation of Na + channels. Several reports have shown that pharmacological blockade of Na + channels inhibits glucagon secretion [11,14,18,31]. Given that we had observed an augmentation of [Ca 2+ ] i associated with enhanced glucagon secretion upon inhibition of HCN channels, we hypothesised that Na + channels might mediate these effects.…”

Section: Discussionmentioning

confidence: 83%

“…T-and N-type Ca 2+ channels and tetrodotoxin (TTX)-sensitive Na + channels are also important in the regulation of alpha cell electrical activity [11,[13][14][15][16][17]. One important feature of these alpha cell ion channels is their voltage-dependent inactivation when the cell membrane is depolarised [14,17,18]. Accordingly, a model for glucagon secretion has been proposed that highlights the important roles of ion channels in regulating glucagon secretion.…”

mentioning

confidence: 99%

“…However, when the membrane potential is depolarised (e.g. K ATP channels close under high glucose conditions), this will voltage-inactivate the Na + and T-and N-type Ca 2+ channels, resulting in the cessation of action potential firing and suppression of glucagon secretion [10,11,14,18]. On the other hand, when the alpha cell membrane potential is excessively hyperpolarised (e.g.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Presence of functional hyperpolarisation-activated cyclic nucleotide-gated channels in clonal alpha cell lines and rat islet alpha cells

Zhang

Zhang²,

Gyulkhandanyan

et al. 2008

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis The hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels, discovered initially in cardiac and neuronal cells, mediate the inward pacemaker current (I f or I h ). Recently, we have demonstrated the presence of HCN channels in pancreatic beta cells. Here, we aim to examine the presence and function of HCN channels in glucagon-secreting alpha cells. Methods RT-PCR and immunocytochemistry were used to examine the presence of HCN channels in alpha cells. Whole-cell patch-clamp, calcium imaging and glucagon secretion experiments were performed to explore the function of HCN channels in alpha cells. Results HCN transcripts and proteins were detected in alpha-TC6 cells and dispersed rat alpha cells. Patch-clamp recording showed hyperpolarisation-activated currents in alpha-TC6 cells, which could be blocked by HCN channel inhibitor ZD7288. Glucagon secretion RIA studies demonstrated that at both low and high glucose concentrations (2 and 20 mmol/l), ZD7288 significantly enhanced glucagon secretion in alpha-TC6 and IN-R1-G9 cell lines. Conversely, activation of HCN channels by lamotrigine significantly suppressed glucagon secretion at the low glucose concentration. Calcium imaging studies showed that blockade of HCN channels by ZD7288 significantly increased intracellular calcium in alpha-TC6 cells, while lamotrigine or the Na + channel blocker tetrodotoxin suppressed the effect of ZD7288 on intracellular calcium. Furthermore, we found the HCN channel inhibitors ZD7288 and cilobradine both significantly increased glucagon secretion from rat islets. Conclusions/interpretation These results suggest a potential role for HCN channels in regulation of glucagon secretion via modulating Ca 2+ and Na + channel activities.

show abstract

Section: Discussionmentioning

confidence: 83%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Presence of functional hyperpolarisation-activated cyclic nucleotide-gated channels in clonal alpha cell lines and rat islet alpha cells

Zhang

Zhang²,

Gyulkhandanyan

et al. 2008

Diabetologia

View full text Add to dashboard Cite

show abstract

“…Inhibition of alpha cell Kv currents may then be expected to prolong or enhance action potential firing and glucagon secretion at low glucose concentrations. However, one study reports that the general Kv channel inhibitor 4-aminopyridine inhibited glucagon secretion [17]. Given the complex regulation of alpha cell function and previous observations that depolarisation of alpha cells may inhibit rather than stimulate alpha cell action potential firing and glucagon release [3,18], the role of the hyperpolarising Kv current in alpha cell function is far from clear.…”

Section: Introductionmentioning

confidence: 99%

Voltage-dependent K+ channels are positive regulators of alpha cell action potential generation and glucagon secretion in mice and humans

2010

View full text Add to dashboard Cite

Aims/hypothesis The regulation of glucagon secretion from alpha cells is poorly understood. Since action potential firing at low glucose is required for glucagon secretion, we hypothesised that voltage-dependent K + (Kv) currents limit glucagon secretion under these conditions, similarly to their role in insulin secretion. Methods Kv currents and action potential firing of mouse and human alpha cells, identified by immunostaining, were examined by whole-cell patch-clamp. Glucagon secretion from mouse and human islets was measured by ELISA. Results Kv current density was 35% larger in alpha than in beta cells. Alpha cell Kv channels were sensitive to block by tetraethylammonium (TEA) and 4-aminopyridine. Surprisingly, Kv channel inhibition reduced glucagon release to the same extent as glucose. Robust action potential firing was observed in beta cells when ATP-sensitive K + channels were closed, but in alpha cells a negative current (−8 pA) injection was required for action potential firing. TEA (0.5 mmol/l) impaired alpha cell action potential firing, which could be restored by further hyperpolarising current injection (−16 pA). Kv currents were more sensitive to the Kv2 inhibitor stromatoxin (100 nmol/l) in mouse (80%) than in human (45%) alpha cells. Finally, the maxi-K (BK) channel inhibitor iberiotoxin (100 nmol/l) blocked 55% of the current in human alpha cells and inhibited glucagon release from human islets. Conclusions/interpretation Kv currents in alpha cells are positive regulators of glucagon secretion. These currents, mediated by Kv2 and BK channels, limit membrane depolarisation, and prevent inactivation of alpha cell action potentials and suppression of glucagon release.

show abstract

“…It has been suggested that K þ ATP channels participate in the regulation of GCG secretion by glucose, since immunohistochemical and electrophysiological studies have detected K þ ATP channels in rat pancreatic alpha cells [7] and glucose and sulfonylurea effects on GCG secretion are deficient in SUR1 −/− mice [8]. Other studies, in the rat, suggest that only a minority of alpha cells have functional K þ ATP channels [9].…”

Section: Discussionmentioning

confidence: 99%

Low levels of glucose transporters and % MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX! % MathType!MTEF!2!1!+- % feaaeaart1ev0aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbbjxAHX % garmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy0Hgip5wz % aebbnrfifHhDYfgasaacH8qrps0lbbf9q8WrFfeuY-Hhbbf9v8qqaq % Fr0xc9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq-He9q8qq % Q8frFve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeWaeaaakeaaca % WGlbWaa0baaSqaaiaadgeacaWGubGaamiuaaqaaiabgUcaRaaaaaa!3BE3! $$ K^{ + }_{{ATP}} $$ channels in human panc

et al. 2007

View full text Add to dashboard Cite

Aims/hypothesis Although cells expressing insulin are detected early in human fetal development, islets isolated from fetal pancreases show poor insulin secretory responses to glucose, which may be the result of deficient glucose sensing. We have used dual and triple immunolabelling of human fetal and adult pancreas sections to investigate the presence of proteins that participate in glucose sensing in the pancreatic beta cell, namely glucose transporter 1 (GLUT 1, also known as SLC2A1), glucose transporter 2 (GLUT2, also known as SLC2A2), glucokinase (GCK) and inwardly rectifying K + channel (KIR6.2, also known as KCNJ11) and sulphonylurea receptor 1 (SUR1, also known as ABCC8) subunits of ATP-sensitive K + channels (K þ ATP channels). Materials and methods Pancreases obtained with ethical approval from human fetuses from 11 to 36 weeks of gestation, from infants and from adults were formalin-fixed and embedded in paraffin. Sections were labelled with antibodies to proteins of interest. Co-production of antigens was examined by dual and triple immunolabelling. Results GLUT2 and K þ ATP channel labelling was detected in the 11-week pancreas, but largely within the pancreatic epithelium, whereas no labelling for GLUT1 was observed. From 15 weeks, GLUT1, GCK and K þ ATP channel labelling was detected in an increasing proportion of insulin-positive cells and epithelial labelling with K þ ATP channel antibodies diminished. GLUT2 was seen in the majority of beta cells only after 7 months of age. Conclusions/interpretation The results demonstrate that only a subpopulation of beta cells in the human fetal pancreas produce all key elements of the glucose-sensing apparatus, which may contribute to poor secretory responses in early life.

show abstract

ATP-Sensitive K+ Channel–Dependent Regulation of Glucagon Release and Electrical Activity by Glucose in Wild-Type and SUR1−/− Mouse α-Cells

Cited by 153 publications

References 48 publications

Presence of functional hyperpolarisation-activated cyclic nucleotide-gated channels in clonal alpha cell lines and rat islet alpha cells

Presence of functional hyperpolarisation-activated cyclic nucleotide-gated channels in clonal alpha cell lines and rat islet alpha cells

Voltage-dependent K+ channels are positive regulators of alpha cell action potential generation and glucagon secretion in mice and humans

Contact Info

Product

Resources

About