The 5-HT2 receptor in brain: recent biochemical and molecular biological developments and new perspectives in its regulation.

Radioligand binding as well as molecular biological studies revealed an heterogeneity of serotonin (5-HT) receptors in the central nervous system. The early availability of specific antagonists for the serotonin-2 (5-HT2) receptor subtype (spiperone, ketanserin and ritanserin represented an important step towards the biochemical, physiological and, more recently, molecular characterization of 5-HT2 receptors in brain. Though they are unevenly distributed in different brain areas, they are highly expressed in the frontal cortex. Based on radioligand studies, either two different 5-HT2 receptors or one 5-HT2 receptor with two different affinity states might exist. Molecular biological studies revealed that the 5-HT2 receptor belongs to the G-protein receptor superfamily and the 5-HT2 receptor clone encodes a single-subunit protein containing approximately 450 amino acids arranged in seven interconnected transmembrane segments. Recent studies suggested that 5-HT itself might not represent the endogenous ligand for the 5-HT2 receptor. Isolation and purification of an endogenous peptide of mol. wt 6-8 kDa with affinity for [3H]ketanserin recognition sites further supports this possibility. The rapid advances in the molecular understanding of the 5-HT2 receptor and its putative endogenous ligand may have significant implications in the actual debate on the classification of the 5-HT2 receptor subtypes.