Double immunohistochemical staining detected inositol 1, 4, 5-trisphosphate receptor type 2 immunoreactivity (IP 3 R2 IR) and chromogranin A-like immunoreactivity (CgA-like IR) on the same sections prepared from the isolated and perfused submandibular gland of rat. In the control sections prepared from resting state, an intense IP 3 R2 IR was localized at the apical pole of granulated duct cell containing CgA-like IR. Electron-microscopically, the granular cells in the resting state stored numerous membrane-bound granules in the apical cytoplasm. The combined stimulation with 1 μM noradrenaline and 0.1 μM acetylcholine caused immediate maximum increase in secretory response (CgA-like IR secretion, flow, and protein secretion). When the sections were prepared from the gland at the peak of secretory response, the apically converged IP 3 R2 IR became diffuse and indistinguishable. Ultrastructure of the maximally stimulated cells exhibited extensive compound exocytosis in the apical half of the granular duct cells. The secretory responses to the combined stimulation were significantly inhibited by 100 μM 2-aminoethyl diphenylborinate, an inhibitory modulator of IP 3 -mediated Ca 2 + release from intracellular stores, and the intense IP 3 R2 IR was well preserved in the apical pole of granular duct cells containing CgA-like IR. These results may be compatible with the view that the divergence of apically convergent IP 3 R2 with the progress of compound exocytosis may result in decay of [Ca 2 + ], due to divergence of IP 3 R2-sensitive Ca 2 + pool, and this may provide a novel paradigm for desensitization of G protein-coupled signaling system.