Tolbutamide stimulates exocytosis of glucagon by inhibition of a mitochondrial‐like ATP‐sensitive K+ (KATP) conductance in rat pancreatic A‐cells
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1. Capacitance measurements were used to examine the effects of the sulphonylurea tolbutamide on Ca2+-dependent exocytosis in isolated glucagon-secreting rat pancreatic A-cells. 2. When applied extracellularly, tolbutamide stimulated depolarization-evoked exocytosis 4.2-fold without affecting the whole-cell Ca2+ current. The concentration dependence of the stimulatory action was determined by intracellular application through the recording pipette. Tolbutamide produced a concentration-dependent increase in cell capacitance. Half-maximal stimulation was observed at 33 microM and the maximum stimulation corresponded to a 3.4-fold enhancement of exocytosis. 3. The stimulatory action of tolbutamide was dependent on protein kinase C activity. The action of tolbutamide was mimicked by the general K+ channel blockers TEA (10 mM) and quinine (10 microM). A similar stimulation was elicited by 5-hydroxydecanoate (5-HD; 10 microM), an inhibitor of mitochondrial ATP-sensitive K+ (KATP) channels. 4. Tolbutamide-stimulated, but not TEA-induced, exocytosis was antagonized by the K+ channel openers diazoxide, pinacidil and cromakalim. 5. Dissipating the transgranular K+ gradient with nigericin and valinomycin inhibited tolbutamide- and Ca2+-evoked exocytosis. Furthermore, tolbutamide- and Ca2+-induced exocytosis were abolished by the H+ ionophore FCCP or by arresting the vacuolar (V-type) H+-ATPase with bafilomycin A1 or DCCD. Finally, ammonium chloride stimulated exocytosis to a similar extent to that obtained with tolbutamide. 6. We propose that during granular maturation, a granular V-type H+-ATPase pumps H+ into the secretory granule leading to the generation of a pH gradient across the granular membrane and the development of a positive voltage inside the granules. The pumping of H+ is facilitated by the concomitant exit of K+ through granular K+ channels with pharmacological properties similar to those of mitochondrial KATP channels. Release of granules that have been primed is then facilitated by the addition of K+ channel blockers. The resulting increase in membrane potential promotes exocytosis by unknown mechanisms, possibly involving granular alkalinization.
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Tolbutamide stimulates electrical activity and exocytosis of glucagon in isolated rat alpha cells.
“Accordingly, tolbutamide stimulates the electrical activity [43] and exocytosis of glucagon [45] in isolated rat alpha cells”
From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [45]
Depolarization by tolbutamide-induced closure of KATP channels increases electrical activity, [Ca2+]i, exocytosis, and secretion in rat alpha-cells.
“Depolarization by tolbutamideinduced closure of the K ATP channels thus increases the electrical activity (24), [Ca 2ϩ ] i (8), exocytosis (28), and secretion (8) in rat ␣-cells”
From Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations (2006) · cites this paper as [28]
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Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells
Vieira, E., Salehi, A., & Gylfe, E. (2007) · Diabetologia · doi:10.1007/s00125-006-0511-1 · Cited by 218 · see citing works
Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification
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Self-citationParadoxical Stimulation of Glucagon Secretion by High Glucose Concentrations
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- Authors
- Høy, M., Olsen, H. L., Bokvist, K., Buschard, K., Barg, S., Rorsman, P., & Gromada, J.
- Affiliations
- Novo Nordisk (Denmark) (DK)
- Lund University (SE)
- Corresponding author
- Gromada, Jesper
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2000-08
- Volume
- 527
- Issue
- 1
- Pages
- 109-120
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC2270047
- OpenAlex
- W2087132310
- Cited by
- 32
- References
- 27
- Citations by year
- 2020: 1 · 2015: 1 · 2013: 2 · 2012: 1
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- tolbutamide, glucagon secretion, pancreatic A cells, exocytosis, mitochondrial ATP-sensitive potassium channel, ATP-sensitive potassium channels, protein kinase C, V-type H+-ATPase, secretory granule maturation, sulfonylureas, potassium channel blockers, 5-hydroxydecanoate, diazoxide
- MeSH terms
- Animals, Calcium, Electric Conductivity, Exocytosis, Glucagon, Proton-Translocating ATPases, Hydrogen-Ion Concentration, Ionophores, Islets of Langerhans, Male, Membrane Potentials, Membrane Proteins, Models, Biological, Pituitary Gland, Potassium, Protein Kinase C, Rats, Inbred Lew, Sulfonylurea Compounds, Tolbutamide, Potassium Channels, Rats, Sprague-Dawley, Cell Culture Techniques, Vacuolar Proton-Translocating ATPases, Rats
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