Multiple mechanisms of serotonin 5-HT₂ receptor desensitization

Desensitization of serotonin 5-HT₂ receptor-mediated enhancement of the methyl-D-aspartate (NMDA) depolarization was studied in rat cortical neurons. Serotonin and (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced long term desensitization. Staurosporine, a nonspecific protein kinase C inhibitor, potentiated the serotonin and DOI facilitation, suggesting acute desensitization was operative. In the case of DOI, long term desensitization was prevented by staurosporine. Activators of protein kinase C abolished the serotonin facilitation, an action prevented by straurosporine. Concanavalin A potentiated the facilitation at 100 μM, but not 30 μM serotonin, suggesting these receptors undergo dose dependent internalization. Calmodulin antagonists prevent long term desensitization induced by serotonin. The depolarization induced by NMDA alone was not altered by straurosporine, protein kinase C activators, concanavalin A or calmodulin antagonists. Serotonin at 100 μM, but not 30 μM, induced heterologous desensitization of phenylephrine and carbachol induced facilitation of the NMDA depolarization. We conclude that serotonin 5-HT₂ receptors both induce and undergo several forms of desensitization.