Amplification of exocytosis by Ca2+-induced Ca2+ release in INS-1 pancreatic beta cells

doi:10.1113/jphysiol.2002.029959

Amplification of exocytosis by Ca²⁺-induced Ca²⁺ release in INS-1 pancreatic $beta$ cells

Guoxin Kang and George G. Holz

Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, USA

Functional coupling between Ca²⁺-induced Ca²⁺ release (CICR) and quantal exocytosis in 5-hydroxytryptamine-loaded INS-1 $beta$ cells was assessed through the use of carbon fibre amperometry in combination with Fura-2. CICR was evoked by the glucagon-like-peptide-1 (GLP-1) receptor agonist exendin-4 (Ex-4) and was accompanied by quantal secretory events appearing as amperometric current spikes time-locked to the increase of [Ca²⁺]_i. The action of Ex-4 was reproduced by treatment with caffeine, and the source of Ca²⁺ serving as a stimulus for exocytosis originated from ryanodine and thapsigargin-sensitive Ca²⁺ stores. Two distinct patterns of exocytosis occurred within 5 s following the initiation of CICR. Non-summating exocytosis (NS-type) was defined as multiple asynchronous current spikes, and the half-height duration of each spike was 12-48 ms. Summating exocytosis (S-type) was defined as a cluster of spikes. It generated a macroscopic current, the half-height duration of which was 243-682 ms. The release charge of S-type exocytosis was 3.2-fold greater than that of NS-type when measured 2 s following the initiation of secretion. NS-type exocytosis was observed frequently under conditions in which the basal Ca²⁺ concentration ([Ca²⁺]_B) was low (75-150 nM), whereas S-type exocytosis predominated under conditions in which the [Ca²⁺]_B was elevated (200-275 nM). Depolarization-induced Ca²⁺ influx triggered NS-type exocytosis in most cells tested, irrespective of [Ca²⁺]_B. It is concluded that CICR is a highly effective stimulus for exocytosis in INS-1 cells. The increase of [Ca²⁺]_i that accompanies CICR stimulates the asynchronous release of a small number of secretory granules under conditions of low [Ca²⁺]_B. When [Ca²⁺]_B is slightly elevated, CICR targets a much larger pool of secretory granules that undergo summating exocytosis. The transition from NS-type to S-type exocytosis may represent an amplification mechanism for Ca²⁺-dependent exocytosis.

This article has been cited by other articles:

L. S. Ramos, J. H. Zippin, M. Kamenetsky, J. Buck, and L. R. Levin
Glucose and GLP-1 Stimulate cAMP Production via Distinct Adenylyl Cyclases in INS-1E Insulinoma Cells
J. Gen. Physiol., August 25, 2008; 132(3): 329 - 338.
[Abstract] [Full Text] [PDF]

Y. Li, I. B. M. Konings, J. Zhao, L. S. Price, E. de Heer, and P. M. T. Deen
Renal expression of exchange protein directly activated by cAMP (Epac) 1 and 2
Am J Physiol Renal Physiol, August 1, 2008; 295(2): F525 - F533.
[Abstract] [Full Text] [PDF]

J. E. Geiger and N. S. Magoski
Ca2+-Induced Ca2+ Release in Aplysia Bag Cell Neurons Requires Interaction Between Mitochondrial and Endoplasmic Reticulum Stores
J Neurophysiol, July 1, 2008; 100(1): 24 - 37.
[Abstract] [Full Text] [PDF]

S. Tsunekawa, N. Yamamoto, K. Tsukamoto, Y. Itoh, Y. Kaneko, T. Kimura, Y. Ariyoshi, Y. Miura, Y. Oiso, and I. Niki
Protection of pancreatic {beta}-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies
J. Endocrinol., April 1, 2007; 193(1): 65 - 74.
[Abstract] [Full Text] [PDF]

G. G. Holz, G. Kang, M. Harbeck, M. W. Roe, and O. G. Chepurny
Cell physiology of cAMP sensor Epac
J. Physiol., November 15, 2006; 577(1): 5 - 15.
[Abstract] [Full Text] [PDF]

K.-P. Yip
Epac-mediated Ca2+ mobilization and exocytosis in inner medullary collecting duct
Am J Physiol Renal Physiol, October 1, 2006; 291(4): F882 - F890.
[Abstract] [Full Text] [PDF]

G. Kang, O. G. Chepurny, B. Malester, M. J. Rindler, H. Rehmann, J. L. Bos, F. Schwede, W. A. Coetzee, and G. G. Holz
cAMP sensor Epac as a determinant of ATP-sensitive potassium channel activity in human pancreatic {beta} cells and rat INS-1 cells
J. Physiol., June 15, 2006; 573(3): 595 - 609.
[Abstract] [Full Text] [PDF]

G. Kang, O. G Chepurny, M. J Rindler, L. Collis, Z. Chepurny, W.-h. Li, M. Harbeck, M. W Roe, and G. G Holz
A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic {beta} cells
J. Physiol., July 1, 2005; 566(1): 173 - 188.
[Abstract] [Full Text] [PDF]

R. Bertram and A. Sherman
Filtering of Calcium Transients by the Endoplasmic Reticulum in Pancreatic {beta}-Cells
Biophys. J., December 1, 2004; 87(6): 3775 - 3785.
[Abstract] [Full Text] [PDF]

N. M. Doliba, W. Qin, M. Z. Vatamaniuk, C. Li, D. Zelent, H. Najafi, C. W. Buettger, H. W. Collins, R. D. Carr, M. A. Magnuson, et al.
Restitution of defective glucose-stimulated insulin release of sulfonylurea type 1 receptor knockout mice by acetylcholine
Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E834 - E843.
[Abstract] [Full Text] [PDF]

A. Merglen, S. Theander, B. Rubi, G. Chaffard, C. B. Wollheim, and P. Maechler
Glucose Sensitivity and Metabolism-Secretion Coupling Studied during Two-Year Continuous Culture in INS-1E Insulinoma Cells
Endocrinology, February 1, 2004; 145(2): 667 - 678.
[Abstract] [Full Text] [PDF]

G. G. Holz
Epac: A New cAMP-Binding Protein in Support of Glucagon-Like Peptide-1 Receptor-Mediated Signal Transduction in the Pancreatic {beta}-Cell
Diabetes, January 1, 2004; 53(1): 5 - 13.
[Abstract] [Full Text] [PDF]

B. Ahren, J. J. Holst, and A. Mari
Characterization of GLP-1 Effects on {beta}-Cell Function After Meal Ingestion in Humans
Diabetes Care, October 1, 2003; 26(10): 2860 - 2864.
[Abstract] [Full Text] [PDF]

T. K. Graves and P. M. Hinkle
Ca2+-Induced Ca2+ Release in the Pancreatic {beta}-Cell: Direct Evidence of Endoplasmic Reticulum Ca2+ Release
Endocrinology, August 1, 2003; 144(8): 3565 - 3574.
[Abstract] [Full Text] [PDF]

G. Kang, J. W. Joseph, O. G. Chepurny, M. Monaco, M. B. Wheeler, J. L. Bos, F. Schwede, H.-G. Genieser, and G. G. Holz
Epac-selective cAMP Analog 8-pCPT-2'-O-Me-cAMP as a Stimulus for Ca2+-induced Ca2+ Release and Exocytosis in Pancreatic beta -Cells
J. Biol. Chem., February 28, 2003; 278(10): 8279 - 8285.
[Abstract] [Full Text] [PDF]