Expression of Voltage-Gated Potassium Channels in Human and Rhesus Pancreatic Islets

Yan, Lizhen; Figueroa, David J.; Austin, Christopher P.; Liu, Yuan; Bugianesi, Randal M.; Slaughter, Robert S.; Kaczorowski, Gregory J.; Köhler, Martin

doi:10.2337/diabetes.53.3.597

Cited by 95 publications

(102 citation statements)

References 51 publications

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“…The second type of K + current is of the delayed-rectifier type and sensitive to TEA and the Kv2.1/2.2 specific antagonist stromatoxin. This confirms a previous study reporting expression of Kv2.2 in human delta cells [17]. Inhibition of the sustained outward K + current using TEA increased action potential duration and amplitude and stimulated/tended to stimulate somatostatin secretion at 1 and 6 mmol/l glucose ( Fig.…”

Section: Discussionsupporting

confidence: 92%

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Somatostatin release, electrical activity, membrane currents and exocytosis in human pancreatic delta cells

et al. 2009

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Aims/hypothesis The aim of this study was to characterise electrical activity, ion channels, exocytosis and somatostatin release in human delta cells/pancreatic islets. Methods Glucose-stimulated somatostatin release was measured from intact human islets. Membrane potential, currents and changes in membrane capacitance (reflecting exocytosis) were recorded from individual human delta cells identified by immunocytochemistry. Results Somatostatin secretion from human islets was stimulated by glucose and tolbutamide and inhibited by diazoxide. Human delta cells generated bursting or sporadic electrical activity, which was enhanced by tolbutamide but unaffected by glucose. Delta cells contained a tolbutamide-insensitive, Ba 2+ -sensitive inwardly rectifying K + current and two types of voltagegated K + currents, sensitive to tetraethylammonium/ stromatoxin (delayed rectifying, Kv2.1/2.2) and 4-aminopyridine (A current). Voltage-gated tetrodotoxin (TTX)-sensitive Na + currents contributed to the action potential upstroke but TTX had no effect on somatostatin release. Delta cells are equipped with Ca 2+ channels blocked by isradipine (L), ω-agatoxin (P/Q) and NNC 55-0396 (T). Blockade of any of these channels interferes with delta cell electrical activity and abolishes glucose-stimulated somatostatin release. Capacitance measurements revealed a slow component of depolarisation-evoked exocytosis sensitive to ω-agatoxin. Conclusions/interpretation Action potential firing in delta cells is modulated by ATP-sensitive K + -channel activity. The membrane potential is stabilised by Ba 2+ -sensitive inwardly rectifying K + channels. Voltage-gated L-and T-type Ca 2+ channels are required for electrical activity, whereas Na + currents and P/Q-type Ca 2+ channels contribute to (but are not necessary for) the upstroke of the action potential. Action potential repolarisation is mediated by A-type and Kv2.1/2.2 K + channels. Exocytosis is tightly linked to Ca 2+ -influx via P/Q-type Ca 2+ channels. Glucose stimulation of somatostatin secretion involves both K ATP channel-dependent and -independent processes.

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Section: Discussionsupporting

confidence: 92%

“…Expression of Kv2.2 and Kv2.1 channels in human islets has been reported previously [13,17]. Stromatoxin reduced the peak and sustained outward currents during 500 ms depolarisations to 0 mV by 62±10% and 96±2%, respectively (p<0.05, n=4), without affecting the A current ( Fig.…”

Section: Immunohistochemical Localisation Of Delta Cells In Human Pansupporting

confidence: 77%

Somatostatin release, electrical activity, membrane currents and exocytosis in human pancreatic delta cells

et al. 2009

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“…The presence of several Kv channel isoforms has been reported in an alpha cell line [6,8], and in human [9] and mouse [10] alpha cells, including mRNA transcript or protein production of Kv2.1, Kv3.1, Kv3.2, Kv3.3, Kv4.3, Kv6.1 and Kv6.3. In human islets, Braun et al [15] reported the presence of mRNA transcript for Kv2.1 and Kv2.2, and although this data is not specific to alpha cells, they also reported high expression of BK channels.…”

Section: Discussionmentioning

confidence: 99%

“…Like insulin-secreting beta cells, alpha cells possess robust voltage-dependent K + (Kv) currents, which are believed to participate in action potential repolarisation [3][4][5][6][7]. Levels of several Kv channel isoforms, including mRNA transcript or protein levels of Kv2.1, Kv3.1, Kv3.2, Kv3.3, Kv4.3, Kv6.1 and Kv6.3, have been reported in alpha cell lines [6,8] and primary human [9] and mouse [10] alpha cells, although the functional contribution of these to alpha cell Kv currents is not well established.…”

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

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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.

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“…Eleven subfamilies of this channel are known to exist in mammals. In a detailed study by Yan and coworkers K v2.1 , K v3.2 , K v6.2 , and K v9.3 were found on β cells whereas K v3.1 and K v6.1 were found on α cells and K v2.2 on δ cells of human islets (Yan et al, 2004). A summary of expression the various K v families in insulinoma cells and rat islets has been compiled by .…”

Section: Potassium Channelsmentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

576

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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Expression of Voltage-Gated Potassium Channels in Human and Rhesus Pancreatic Islets

Cited by 95 publications

References 51 publications

Somatostatin release, electrical activity, membrane currents and exocytosis in human pancreatic delta cells

Somatostatin release, electrical activity, membrane currents and exocytosis in human pancreatic delta cells

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

Mechanisms of action of glucagon-like peptide 1 in the pancreas

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