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Received July 31, 2002
Accepted after revision October 16, 2002
cells
1 Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, USA
2 Associate Professor of Physiology and Neuroscience, Medical Sciences Building Room 442, 550 First Avenue, New York, NY 10016, USA
* To whom correspondence should be addressed. E-mail: holzg01{at}popmail.med.nyu.edu.
Functional coupling between Ca2+-induced Ca2+ release (CICR) and quantal exocytosis in 5-hydroxytryptamine-loaded INS-1 
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 in [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.
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