Serotonin 2A (5-HT2A) Receptor Function: Ligand-Dependent Mechanisms and Pathways

Excerpt

G-protein-coupled receptors or GPCRs have been a major area of study in the past decades. This is not surprising as this group, comprising a thousand-odd proteins, constitutes the largest group of signal transducers across the cell membrane and is also implicated in a vast number of diseases [1]. All major neuromodulators and some fast neurotransmitters act through either a single GPCR or a family of GPCRs, collectively termed a neuromodulator receptor family (such as the serotonin receptor family). This dependence of proper brain function on GPCR signaling is reflected in the fact that most psychiatric diseases implicate one or many malfunctioning GPCRs in their pathophysiology. Consequently, drugs aimed at treating these disorders are primarily targeted to GPCRs.

The serotonin 2A receptor (5-HT_2A) has been implicated in mental disorders with complex etiologies that are still not clearly understood, in processes such as learning and memory, and also in neurogenesis. There are a large number of drugs targeted to this receptor. Though the receptor has been studied largely in relation to its multiple functions in the CNS, high levels of receptor expression in other areas such as the intestine, platelets and endothelial cells suggest that it could play crucial roles in other aspects of physiology. Research shows that some GPCRs, including the 5-HT_2A receptor, exhibit critical differences in aspects of functional regulation from those seen in conventionally studied model GPCRs such as the β-2-adrenergic receptor. The receptor also couples to a number of intracellular signaling cascades, making it an important receptor to study. The 5-HT_2A receptor could well serve as an important alternate paradigm in the study of GPCR function.

The 5-HT_2A receptor was initially identified by hybridization using conserved elements of the cloned 5-HT_2C receptor, followed by functional expression [2,3]. It bears strong similarity in primary sequence to the two other members of its subfamily, i.e., 5-HT_2B and 5-HT_2C. All members of the 5-HT₂ receptor subfamily primarily couple to PLC on activation. As with most GPCRs, 5-HT_2A functional regulation also involves desensitization and resensitization—regulatory processes that help prevent overstimulation and allow recuperation of signaling competence, respectively. Internalization and recycling of the receptor represent two processes that regulate this desensitization and resensitization. The receptor contains numerous recognition motifs for interacting partners to dock and facilitate receptor signaling, desensitization or trafficking. In some GPCRs, these processes are mediated by posttranslational modifications such as phosphorylation of one or more amino acid residues of the receptor. What makes these processes an area of consistent interest in 5-HT_2A research is that drugs, psychotropic or therapeutic, modify many aspects of receptor functionality. Conversely, it has been suggested that the pathophysiology of psychiatric disorders is based on malfunctions in one or more aspects of GPCR function.

The importance of the role played by the 5-HT_2A receptor in mediating CNS function can be seen by its considerable expression in various regions of the CNS and its wide-ranging effects.