L-Histidine decarboxylase (HisDC) is the enzyme catalyzing the formation of histamine from L-histidine. HisDC activity is expressed specifically in mast cells/basophils, endocrine cells in stomach, and histaminergic neurons in brain. As a first step in the analysis of the regulation of HisDC gene expression, we have cloned the cDNA coding for HisDC from a cDNA library of a human basophilic leukemia cell line, KU-812-F. We identified two types of HisDC cDNA, representing the 2.4-kb and 3.4-kb HisDC mRNA constitutively expressed in these cells. Sequence analysis of these cDNA revealed that the 3.4-kb mRNA contains the insert sequence of 824 bases and suggests that both 2.4-kb and 3.4-kb mRNA may represent the alternatively spliced transcripts of the HisDC gene. Using expression plasmids containing a cDNA for each HisDC mRNA, we analyzed the function of possible HisDC isoforms. We show that only the 2.4-kb mRNA encodes functional HisDC and is expressed in human brain and lung. However, we were unable to detect the 3.4-kb mRNA in these tissues. Thus, the 3.4-kb mRNA may be generated by KU-812-F cell-specific splicing of the HisDC gene transcripts. Furthermore, we demonstrated the increase in the level of 2.4-kb HisDC mRNA and HisDC activity in KU-812-F cells following treatment with phorbol 12-myristate 13-acetate.