Priming of insulin granules for exocytosis by granular Cl− uptake and acidification
Author:
Barg Sebastian1, Huang Ping2, Eliasson Lena1, Nelson Deborah J.2, Obermüller Stefanie1, Rorsman Patrik1, Thévenod Frank3, Renström Erik1
Affiliation:
1. Department of Physiological Sciences, Lund University, Sölvegatan 19, SE-223 62 Lund, Sweden 2. University of Chicago, Department of Neurobiology, Pharmacology and Physiology, 947 E. 58th Street, MC 0926, Chicago, IL 60637, USA 3. Physiologisches Institut, Universität des Saarlandes, D-66421 Homburg/Saar, Germany
Abstract
ATP-dependent priming of the secretory granules precedes Ca2+-regulated neuroendocrine secretion, but the exact nature of this reaction is not fully established in all secretory cell types. We have further investigated this reaction in the insulin-secreting pancreatic B-cell and demonstrate that granular acidification driven by a V-type H+-ATPase in the granular membrane is a decisive step in priming. This requires simultaneous Cl− uptake through granular ClC-3 Cl− channels. Accordingly, granule acidification and priming are inhibited by agents that prevent transgranular Cl− fluxes, such as 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) and an antibody against the ClC-3 channels, but accelerated by increases in the intracellular ATP:ADP ratio or addition of hypoglycemic sulfonylureas. We suggest that this might represent an important mechanism for metabolic regulation of Ca2+-dependent exocytosis that is also likely to be operational in other secretory cell types.
Publisher
The Company of Biologists
Reference36 articles.
1. Aizawa, T., Sato, Y., Komatsu, M. and Hashizume, K. (1992). ATP-sensitive K+ channel-independent, insulinotropic action of glucose in the B-cells. Endocr. Regul. 26, 159-162. 2. al-Awqati, Q., Barasch, J. and Landry, D. (1992). Chloride channels of intracellular organelles and their potential role in cystic fibrosis. J. Exp. Biol.172,245-266. 3. Ämmälä, C., Eliasson, L., Bokvist, K., Larsson, O., Ashcroft, F. M. and Rorsman, P. (1993). Exocytosis elicited by action potentials and voltage-clamp calcium currents in individual mouse pancreatic B-cells. J. Physiol. (Lond.)472, 665-688. 4. Ashcroft, F. M. and Rorsman, P. (1995). In The Electrophysiology of Neuroendocrine Cells, Vol. 10 (ed. Heschler, J. and Scherübl, H.), pp. 207-243. Boca Raton, FL, USA: CRC Press. 5. Barg, S., Renström, E., Berggren, P-O., Bertorello, A., Bokvist, K., Braun, M., Eliasson, L., Holmes, W., Köhler, M., Rorsman, P. et al. (1999). The stimulatory action of tolbutamide on Ca2+-dependent exocytosis in pancreatic β cells is mediated by a 65-kDa mdr-like P-glycoprotein. Proc. Natl. Acad. Sci. USA.96, 5539-5544.
Cited by
108 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献
|
|