Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo

Abstract

Visual and auditory hallucinations accompany certain neuropsychiatric disorders, such as schizophrenia, and they also can be induced by the use or abuse of certain drugs. The heptahelical serotonin 2A receptors (5-HT2ARs) are molecular targets for druginduced hallucinations. However, the cellular mechanisms by which the 5-HT2AR mediates these effects are not well understood. Drugs acting at the 5-HT2AR can trigger diverse signaling pathways that may be directed by the chemical properties of the drug. ␤-arrestins are intracellular proteins that bind to heptahelical receptors and represent a point where such divergences in liganddirected functional signaling could occur. Here we compare the endogenous agonist, serotonin, to a synthetic 5-HT2AR hallucinogenic agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), in mice lacking ␤-arrestin-2, as well as in cells lacking ␤-arrestins. In mice, we find that serotonin induces a head twitch response by a ␤-arrestin-2-dependent mechanism. However, DOI invokes the behavior independent of ␤-arrestin-2. The two structurally distinct agonists elicit different signal transduction and trafficking patterns upon activation of 5-HT2AR, which hinge on the presence of ␤-arrestins. Our study suggests that the 5-HT2AR-␤-arrestin interaction may be particularly important in receptor function in response to endogenous serotonin levels, which could have major implications in drug development for treating neuropsychiatric disorders such as depression and schizophrenia.5-HT2A receptor ͉ G protein-coupled receptor ͉ internalization ͉ MAP kinase ͉ schizophrenia

Hallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Senescence-Accelerated Mice

“…A recent study reported that 5-HT2AR signaling can be transduced by the ERK1/2 pathway [18]. The results of the present study indicate that dOI dose-dependently increased the phyosphorylation levels of ERK1/2 in SAMP6 and SAMR1, and that SAMP6 given 0.3 and 1.0 mg/kg dOI showed higher phosphorylation levels of ERK1/2 than SAMR1 given dOI at the same doses.…”

“…These findings suggest that b-arrestin-2 plays a significant role in 5-HT2AR ligand-directed functional signaling and behavioral responsiveness. The head-twitch response induced by 5-HT was previously shown to be greatly attenuated in b-arrestin-2-knockout mice [18]. Moreover, treatment with dOI produced head-twitch responses of equal magnitude in b-arrestin-2-knockout and wild-type mice [18].…”

“…The head-twitch response induced by 5-HT was previously shown to be greatly attenuated in b-arrestin-2-knockout mice [18]. Moreover, treatment with dOI produced head-twitch responses of equal magnitude in b-arrestin-2-knockout and wild-type mice [18]. These data suggest that b-arrestin-2 mediates endogenous agonist-induced head-twitch responses, whereas the synthetic agonist dOI produces this behavior in a b-arrestin-2-independent manner.…”

“…Hallucinogens such as 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (dOI) are potent 5-HT2AR and serotonin receptor 2C (5-HT2CR) agonists, and their effects, which include the stimulation of a head-twitch behavioral response [23], appear to reflect their actions at 5-HT2AR [15,19]. The two agonists have been reported to direct differential signaling via 5-HT2AR [18]. Serotonin (5-HT) induces extracellular signal-regulated kinase 1/2 (ERK1/2) signaling and head-twitch behavior by a b-arrestin-2-dependent mechanism.…”

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

“…It is well known that the 5-HT 2A R can signal through multiple non-G-protein pathways including ␤-arrestins (28,41,42). Therefore, although canonical 5-HT 2A R signaling would be redundant relative to ADP-mediated P2Y 1 activation, alternative signaling pathways downstream of ␤-arrestins, such as ERK1/2 and c-Src, could culminate in ␣IIb␤3 activation (28,(41)(42)(43). Additionally, 5-HT 2A R signaling through arachidonic acid, 2-arachidonylglycerol, calmodulin, or AKT could also synergize with ADP signaling (44 -47).…”