Serotonin 2A (5-HT2A) receptor affects cell–matrix adhesion and the formation and maintenance of stress fibers in HEK293 cells

Abstract

Abstract5-HT2A, a G-protein coupled receptor, is widely expressed in the human body, including in the gastrointestinal tract, platelets and the nervous system. It mediates various functions, for e.g. learning, memory, mood regulation, platelet aggregation and vasoconstriction, but its involvement in cell-adhesion remains largely unknown. Here we report a novel role for 5-HT2A in cell–matrix adhesion.In HEK293 cells, which are loosely adherent, expression and stimulation of human or rat 5-HT2A receptor by agonists such as serotonin or 2,5-dimethoxy-4-iodoamphetamine (DOI) led to a significant increase in adhesion, while inhibition of 5-HT2A by antipsychotics, such as risperidone, olanzapine or chlorpromazine prevented it. 5-HT2A activation gave rise to stress fibers in these cells and was also required for their maintenance. Mechanistically, the 5-HT2A-mediated adhesion was mediated by downstream PKC and Rho signaling. Since 5-HT2A is associated with many disorders such as dementia, depression and schizophrenia, its role in cell–matrix adhesion could have implications for neural circuits.

Overcoming Depression with 5-HT2A Receptor Ligands

“…Receptor Subtype Pharmacological Importance G αi -coupled serotonin receptors; usually decrease the activity of adenylyl cyclase and lower the intracellular cAMP concentration [32] 5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 1E , 5-HT 1F 5-HT 5A , 5-HT 5B Out of all 14 subtypes, the 5-HT 2A receptor has recently gained a lot of interest. This subject has become a hot topic after the recent publication of the Cryo-EM and X-ray structures of the 5-HT 2A receptor complexed with agonist, inverse agonist, and partial agonist, which has brought up a discussion on the pharmacological importance of this subtype's ligands [34][35][36]. This review aims to characterize 5-HT 2A receptors and describe their contribution to depression.…”

“…Human subtype 2A of the 5-HT receptor was cloned in the 1990s and is characterized by 41% and 46% of identity with the 5-HT 2B and 5-HT 2C subtypes. It is worth highlighting that it shares more than 90% of sequence homology with the rat 5-HT 2A receptor, but some significant differences in their functional selectivity, regulation of desensitization, and resensitization can be identified [ 35 ]. In humans, this receptor is encoded by the HTR2A gene, located on chromosome 13 (46.83–46.9 Mb) [ 35 ].…”

“…It is worth highlighting that it shares more than 90% of sequence homology with the rat 5-HT 2A receptor, but some significant differences in their functional selectivity, regulation of desensitization, and resensitization can be identified [ 35 ]. In humans, this receptor is encoded by the HTR2A gene, located on chromosome 13 (46.83–46.9 Mb) [ 35 ]. Out of all 14 subtypes of serotonin receptors, the 5-HT 2A is widely abundant across the central nervous system, with the highest concentration in monoaminergic brainstem levels, such as the median raphe nucleus/dorsal raphe nucleus, the locus coeruleus, and ventral tegmental area—structures involved in the regulation of mood.…”

“…Out of all 14 subtypes, the 5-HT 2A receptor has recently gained a lot of interest. This subject has become a hot topic after the recent publication of the Cryo-EM and X-ray structures of the 5-HT 2A receptor complexed with agonist, inverse agonist, and partial agonist, which has brought up a discussion on the pharmacological importance of this subtype’s ligands [ 34 , 35 , 36 ]. This review aims to characterize 5-HT 2A receptors and describe their contribution to depression.…”

The roles of serotonin in cell adhesion and migration, and cytoskeletal remodeling

“…Several medications are therefore targeted to 5-HT receptors. Recent results from our laboratory suggest that some of the clinically used antipsychotics may modulate adhesion-related processes and F-actin remodeling [57]. Many neuropsychiatric studies, including postmortem brain analysis of schizophrenic patients, have shown expression of synaptic adhesion molecules such as neural cell adhesion molecule (NCAM) to be significantly reduced [58].…”