Genomic clones of rat, guinea pig and human histamine H1 receptors were isolated with bovine H1 receptor cDNA used as a probe. They were all intronless genes. Amino acid sequence homologies among H1 receptors from four species were high in transmembrane domains and intracellular regions adjacent to membrane domains. The human H1 receptor gene was located in the chromosome 3p25. Four polyadenylation signals were found in the 3' noncoding region. TATA box and CACCC sequences, AP-1 binding site-like, AP-2 binding and NF-GMb binding sequences and many other binding sequences for inducers were found in the 5' noncoding region. Two H1 receptor mRNA bands with 3.0- and 3.5-kilobases were expressed in human peripheral tissues. The 5' noncoding region of the human H1 receptor gene possessed promoter activity, and the activity was enhanced 2.5-times by a protein kinase C-activating phorbol ester. H1 receptors in HeLa cells were time- and dose-dependently up-regulated by phorbol ester. This up-regulation was involved in the activation of the H1 receptor gene expression.