Amphiphilic peptides with positive charges such as substance P (SP) and mastoparan (MP) are known to induce exocytosis in rat peritoneal mast cells. To elucidate whether and how intracellular Ca2+ signaling is involved in the peptide-incluced exocytosis, here we investigated the relationships between an increase in intracellular free Ca2+ concentration ([Ca2+](i)) and exocytosis caused by SP and MP. SP and MP induced exocytosis coinciding with an initial rapid and transient [Ca2+](i) increase, but not with a sustained increase. These stimulations were abolished by pertussis toxin, indicating the involvement of the G(i)-family of G proteins in the peptide signaling. Moreover, the [Ca2+](i) increase was shown to accelerate and potentiate exocytosis, suggesting that the transient increase in [Ca2+](i) positively modified exocytotic secretion. However, it was indicated that the signal of [Ca2+](i) increase was not sufficient for the peptide-induced exocytosis, suggesting the participation of alternative mechanisms other than Ca2+ signaling in the pathway. (C) 2008 Elsevier Inc. All rights reserved.