Site-directed mutagenesis and molecular modeling studies of h5-HT7(a) receptor reveal important residues for binding and activation

Serotonin (5-hydroxytryptamine, 5-HT) is a key neurotransmitter implicated in neuropsychiatric disturbance such as depression, anxiety and psychosis. Recent studies on knockout animals and using selective 5-HT7 receptor antagonists have provided strong support that the G-protein-coupled 5-HT7 receptor plays a role in the onset of depression. To better understand the process of ligand binding to and activation of the 5-HT7 receptor and which essential residues are involved, we have used structural modeling of 5-HT7 receptors and site-directed mutagenesis combined with biological assays to identify which amino acids are essential for ligand binding and receptor activation. Important residues have been identified in the 7th transmembrane domain and in the second intracellular loop of the h5-HT7(a) receptor.