Histogranin is a naturally-occurring pentadecapeptide with a structure 80% homologous with that a fragment-(86-100) of histone H4. First isolated from bovine adrenal medulla, the peptide was also shown to be present in the pituitary, brain, adrenal glands, blood plasma, lungs and spleen. At the subcellular level, histogranin is concentrated in secretory vesicles and it is released from perfused bovine adrenal glands 15-35 min after stimulation with carbamylcholine as opposed to catecholamines and [Leu5]enkephalin which are released immediately after stimulation. Rat brain membranes possess specific binding sites for [125I][Ser1]histogranin with characteristics of a receptor, namely high affinity, saturability, reversibility and sensitivity to heat and proteolytic enzyme treatments. Intracerebroventricular injections of synthetic histogranin (10-100 nmol) in mice protect them against N-methyl-D-aspartate (NMDA)-induced convulsions without affecting convulsions induced by (R,S)-alpha-amino-3-hydroxy -5-methyl-4-isoxazole-propionate (AMPA), kainate and bicuculline. The peptide also binds to specific sites on human peripheral blood mononuclear cells and it evokes the release of tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) from isolated rat macrophages in culture. Since the structure of histone H4 is considered as one of the most conservative, it is presumed that histogranin possesses its own precursor and that its gene is distinctly expressed.