Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3.
Priming of insulin secretory granules for release requires intragranular acidification and depends on vesicular Cl(-)-fluxes, but the identity of the chloride transporter/ion channel involved is unknown. We tested the hypothesis that the chloride transport protein ClC-3 fulfills these actions in pan...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2009
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| _version_ | 1797074244781211648 |
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| author | Li, D Jing, X Salehi, A Collins, S Hoppa, M Rosengren, A Zhang, E Lundquist, I Olofsson, C Mörgelin, M Eliasson, L Rorsman, P Renström, E |
| author_facet | Li, D Jing, X Salehi, A Collins, S Hoppa, M Rosengren, A Zhang, E Lundquist, I Olofsson, C Mörgelin, M Eliasson, L Rorsman, P Renström, E |
| author_sort | Li, D |
| collection | OXFORD |
| description | Priming of insulin secretory granules for release requires intragranular acidification and depends on vesicular Cl(-)-fluxes, but the identity of the chloride transporter/ion channel involved is unknown. We tested the hypothesis that the chloride transport protein ClC-3 fulfills these actions in pancreatic beta cells. In ClC-3(-/-) mice, insulin secretion evoked by membrane depolarization (high extracellular K(+), sulfonylureas), or glucose was >60% reduced compared to WT animals. This effect was mirrored by a approximately 80% reduction in depolarization-evoked beta cell exocytosis (monitored as increases in cell capacitance) in single ClC-3(-/-) beta cells, as well as a 44% reduction in proton transport across the granule membrane. ClC-3 expression in the insulin granule was demonstrated by immunoblotting, immunostaining, and negative immuno-EM in a high-purification fraction of large dense-core vesicles (LDCVs) obtained by phogrin-EGFP labeling. The data establish the importance of granular Cl(-) fluxes in granule priming and provide direct evidence for the involvement of ClC-3 in the process. |
| first_indexed | 2024-03-06T23:33:20Z |
| format | Journal article |
| id | oxford-uuid:6ccc6a1c-3304-4dc3-81aa-f5461f558e4a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:33:20Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:6ccc6a1c-3304-4dc3-81aa-f5461f558e4a2022-03-26T19:13:32ZSuppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6ccc6a1c-3304-4dc3-81aa-f5461f558e4aEnglishSymplectic Elements at Oxford2009Li, DJing, XSalehi, ACollins, SHoppa, MRosengren, AZhang, ELundquist, IOlofsson, CMörgelin, MEliasson, LRorsman, PRenström, EPriming of insulin secretory granules for release requires intragranular acidification and depends on vesicular Cl(-)-fluxes, but the identity of the chloride transporter/ion channel involved is unknown. We tested the hypothesis that the chloride transport protein ClC-3 fulfills these actions in pancreatic beta cells. In ClC-3(-/-) mice, insulin secretion evoked by membrane depolarization (high extracellular K(+), sulfonylureas), or glucose was >60% reduced compared to WT animals. This effect was mirrored by a approximately 80% reduction in depolarization-evoked beta cell exocytosis (monitored as increases in cell capacitance) in single ClC-3(-/-) beta cells, as well as a 44% reduction in proton transport across the granule membrane. ClC-3 expression in the insulin granule was demonstrated by immunoblotting, immunostaining, and negative immuno-EM in a high-purification fraction of large dense-core vesicles (LDCVs) obtained by phogrin-EGFP labeling. The data establish the importance of granular Cl(-) fluxes in granule priming and provide direct evidence for the involvement of ClC-3 in the process. |
| spellingShingle | Li, D Jing, X Salehi, A Collins, S Hoppa, M Rosengren, A Zhang, E Lundquist, I Olofsson, C Mörgelin, M Eliasson, L Rorsman, P Renström, E Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3. |
| title | Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3. |
| title_full | Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3. |
| title_fullStr | Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3. |
| title_full_unstemmed | Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3. |
| title_short | Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3. |
| title_sort | suppression of sulfonylurea and glucose induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein clc 3 |
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