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The stimulatory act...
The stimulatory action of tolbutamide on Ca2+-dependent exocytosis in pancreatic beta cells is mediated by a 65-kDa mdr-like P-glycoprotein
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- Barg, Sebastian (author)
- Lund University,Lunds universitet,Islet cell physiology,Forskargrupper vid Lunds universitet,Lund University Research Groups,Department of Physiological Sciences, Lund University, Lund
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- Renström, Erik (author)
- Lund University,Lunds universitet,Institutionen för kliniska vetenskaper, Malmö,Medicinska fakulteten,Department of Clinical Sciences, Malmö,Faculty of Medicine,Department of Physiological Sciences, Lund University, Lund
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- Berggren, P O (author)
- Karolinska Institutet
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- Bertorello, A (author)
- Karolinska Institutet
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- Bokvist, K (author)
- Novo Nordisk AyS, Bagsvaerd
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- Braun, M (author)
- Physiologisches Institut, Universität des Saarlandes, HomburgySaar
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- Eliasson, Lena (author)
- Lund University,Lunds universitet,Institutionen för kliniska vetenskaper, Malmö,Medicinska fakulteten,Department of Clinical Sciences, Malmö,Faculty of Medicine,Department of Physiological Sciences, Lund University, Lund
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- Holmes, W E (author)
- Novo Nordisk AyS, Bagsvaerd
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- Kohler, M (author)
- Karolinska Institutet
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- Rorsman, Patrik (author)
- Lund University,Lunds universitet,Islet cell physiology,Forskargrupper vid Lunds universitet,Lund University Research Groups,Department of Physiological Sciences, Lund University, Lund
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- Thevenod, F (author)
- Physiologisches Institut, Universität des Saarlandes, HomburgySaar
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(creator_code:org_t)
- Proceedings of the National Academy of Sciences, 1999
- 1999
- English.
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In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 96:10, s. 5539-5544
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Abstract
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- Intracellular application of the sulfonylurea tolbutamide during whole-cell patch-clamp recordings stimulated exocytosis >5-fold when applied at a cytoplasmic Ca2+ concentration of 0.17 microM. This effect was not detectable in the complete absence of cytoplasmic Ca2+ and when exocytosis was elicited by guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS). The stimulatory action could be antagonized by the sulfonamide diazoxide, by the Cl--channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), by intracellular application of the antibody JSB1 [originally raised against a 170-kDa multidrug resistance (mdr) protein], and by tamoxifen (an inhibitor of the mdr- and volume-regulated Cl- channels). Immunocytochemistry and Western blot analyses revealed that JSB1 recognizes a 65-kDa protein in the secretory granules. This protein exhibited no detectable binding of sulfonylureas and is distinct from the 140-kDa sulfonylurea high-affinity sulfonylurea receptors also present in the granules. We conclude that (i) tolbutamide stimulates Ca2+-dependent exocytosis secondary to its binding to a 140-kDa high-affinity sulfonylurea receptor in the secretory granules; and (ii) a granular 65-kDa mdr-like protein mediates the action. The processes thus initiated culminate in the activation of a granular Cl- conductance. We speculate that the activation of granular Cl- fluxes promotes exocytosis (possibly by providing the energy required for membrane fusion) by inducing water uptake and an increased intragranular hydrostatic pressure.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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- art (subject category)
- ref (subject category)
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- By the author/editor
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Barg, Sebastian
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Renström, Erik
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Berggren, P O
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Bertorello, A
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Bokvist, K
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Braun, M
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show more...
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Eliasson, Lena
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Holmes, W E
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Kohler, M
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Rorsman, Patrik
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Thevenod, F
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Proceedings of t ...
- By the university
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Lund University
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Uppsala University
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Karolinska Institutet