Abstract

Among the four G-protein coupled receptors (H1-H4) identified as the mediators of the biological effects of histamine, the H3 receptor (H3R) is distinguished for its almost exclusive expression in the nervous system and the large variety of isoforms generated by alternative splicing of the corresponding mRNA. Additionally, it exhibits dual functionality as auto- and hetero-receptor, and this enables H3Rs to modulate the histaminergic and other neurotransmitter systems. The cloning of the H3R cDNA in 1999 by Lovenberg et al. allowed for detailed studies of its molecular aspects. In this work we review the characteristics of the H3R, namely its structure, constitutive activity, isoforms, signal transduction pathways, regional differences in expression and localization, selective agonists, antagonists and inverse agonists, dimerization with other neurotransmitter receptors, and the main pre- and post-synaptic effects resulting from its activation. The H3R has attracted interest as a potential drug target for the treatment of several important neurological and psychiatric disorders such as Alzheimer's and Parkinson's diseases, Gilles de la Tourette's syndrome and addiction.