Phylogeny, Gene Structure, Expression, and Signaling

The histamine H₃ receptor (H₃R) gene structure is well preserved in vertebrate evolution. H₃R is best known as a central nervous system receptor, although its expression has also been demonstrated in peripheral organs such as the gut, heart, and skin. Hypothalamic histaminergic tuberomamillary nucleus neurons protect hippocampal neurons in vitro against kainic acid-induced damage, and the effect is specific for histamine in this system. Because H₃R activation is connected to regulation of Ca²⁺ channels and signaling cascades are related to plasticity, such as the mitogen-activated protein kinase and serine-threonine kinase systems, histamine through H₃R is potentially important in either protection of neurons against damage or cell death signaling. In the prefrontal cortex, three histamine receptors show laminar preference in their mRNA expression patterns. The zebrafish receptor has also three exons, and the protein sequence shows 42–50% similarity to mouse, rat, dog, and human receptors.