Membrane Potential-Dependent Inactivation of Voltage-Gated Ion Channels in α-Cells Inhibits Glucagon Secretion From Human Islets
| Autor: | Stefan Amisten, Caroline E. Ward, Paul Johnson, Quan Zhang, Matthias Braun, Patrik Rorsman, Jonathan N. Walker, Makoto Shigeto, Reshma Ramracheya |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
Potassium Channels Tolbutamide Endocrinology Diabetes and Metabolism Cell Culture Techniques 030209 endocrinology & metabolism Tetrodotoxin Glucagon Membrane Potentials Islets of Langerhans 03 medical and health sciences 0302 clinical medicine Chlorides Internal medicine Insulin Secretion Internal Medicine medicine Humans Insulin Repolarization 030304 developmental biology Membrane potential 0303 health sciences Voltage-gated ion channel Chemistry Glucagon secretion Depolarization Potassium channel Glucose Endocrinology Islet Studies Glucagon-Secreting Cells Zinc Compounds Calcium Somatostatin Ion Channel Gating medicine.drug |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | OBJECTIVE To document the properties of the voltage-gated ion channels in human pancreatic α-cells and their role in glucagon release. RESEARCH DESIGN AND METHODS Glucagon release was measured from intact islets. [Ca2+]i was recorded in cells showing spontaneous activity at 1 mmol/l glucose. Membrane currents and potential were measured by whole-cell patch-clamping in isolated α-cells identified by immunocytochemistry. RESULTS Glucose inhibited glucagon secretion from human islets; maximal inhibition was observed at 6 mmol/l glucose. Glucagon secretion at 1 mmol/l glucose was inhibited by insulin but not by ZnCl2. Glucose remained inhibitory in the presence of ZnCl2 and after blockade of type-2 somatostatin receptors. Human α-cells are electrically active at 1 mmol/l glucose. Inhibition of KATP-channels with tolbutamide depolarized α-cells by 10 mV and reduced the action potential amplitude. Human α-cells contain heteropodatoxin-sensitive A-type K+-channels, stromatoxin-sensitive delayed rectifying K+-channels, tetrodotoxin-sensitive Na+-currents, and low-threshold T-type, isradipine-sensitive L-type, and ω-agatoxin-sensitive P/Q-type Ca2+-channels. Glucagon secretion at 1 mmol/l glucose was inhibited by 40–70% by tetrodotoxin, heteropodatoxin-2, stromatoxin, ω-agatoxin, and isradipine. The [Ca2+]i oscillations depend principally on Ca2+-influx via L-type Ca2+-channels. Capacitance measurements revealed a rapid ( CONCLUSIONS Human α-cells are electrically excitable, and blockade of any ion channel involved in action potential depolarization or repolarization results in inhibition of glucagon secretion. We propose that voltage-dependent inactivation of these channels underlies the inhibition of glucagon secretion by tolbutamide and glucose. |
| Databáze: | OpenAIRE |
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