Serotonin receptor signaling and regulation via β-arrestins

Serotonin receptors are the product of 15 distinct genes, 14 of which are G protein-coupled receptors. These receptors are expressed in a wide range of cell types, including distinct neuronal populations, and promote diverse functional responses in multiple organ systems. These receptors are important for mediating the in vivo effects of their cognate neurotransmitter, serotonin, as well as the endogenous tryptamines. In addition, the actions of many drugs are mediated, either directly or indirectly, through serotonin receptors, including antidepressants, antipsychotics, anxiolytics, sleep aids, migraine therapies, gastrointestinal therapeutics and hallucinogenic drugs. It is becoming increasingly evident that serotonin receptors can engage in differential signaling that is determined by the chemical nature of the ligand and that ligands that demonstrate a predilection for inducing a particular signaling cascade are considered to have "functional selectivity". The elucidation of the cellular signaling pathways that mediate the physiological responses to serotonin and other agonists is an active area of investigation and will be an onward-looking focal point for determining how to effectively and selectively promote beneficial serotonergic mimicry while avoiding unwanted clinical side effects. This review highlights the modulation of serotonin 2A, 2C, and four receptors by β-arrestins, which may represent a fulcrum for biasing receptor responsiveness in vivo.