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.