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Differential regulation of serotonin 2A receptor responsiveness by agonist-directed interactions with beta-arrestin2

Schmid, Cullen L.

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2011, Doctor of Philosophy, Ohio State University, Neuroscience Graduate Studies Program.
The G protein-coupled, serotonin 2A (5-HT2A) receptor is a major drug target for the treatment of a number of mental health disorders, including schizophrenia, anxiety and depression. In addition to modulating several of the physiological effects of the neurotransmitter serotonin, activation of the 5-HT2A receptor mediates the psychotomimetic effects of serotonergic hallucinogenic drugs, such as lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine (DOI) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Though hallucinogens are agonists at the 5-HT2A receptor, not all 5-HT2A receptor agonists induce hallucinations in humans, including the endogenous ligand serotonin. Therefore, the activation of the 5-HT2A receptor can result in different biological responses depending upon the chemical nature of the ligand, a concept that has been referred to as “functional selectivity.” One way in which ligands can induce differential signaling at GPCRs is through interactions with beta-arrestins, which can act to dampen or facilitate receptor signaling cascades or mediate the internalization of receptors into intracellular vesicles. The overarching hypothesis of this dissertation is that the interaction between the regulatory protein, beta-arrestin2, and the 5-HT2A receptor is a critical point in the divergence of agonist-directed 5-HT2A receptor responsiveness. Using mice lacking beta-arrestin2, we evaluate 5-HT2A receptor trafficking and signaling in vivo for serotonin, the hallucinogenic agonists DOI and 5-MeO-DMT and the endogenous, hallucinogenic metabolite of serotonin, N-methylserotonin. We find that beta-arrestin2 mediates 5-HT2A receptor trafficking in primary neuronal cultures and can facilitate 5-HT2A receptor-mediated signaling cascades in the mouse frontal cortex, although its role is entirely dependent upon the agonist acting at the receptor. Serotonin requires beta-arrestins to internalize the 5-HT2A receptor and to scaffold the signaling kinases Akt and Src to the receptor. The formation of this receptor scaffold results in an increase in Akt activity, which is disrupted in the absence of beta-arrestin2, while the reintroduction of beta-arrestin2 into primary cortical neurons rescues serotonin-induced phosphorylation of Akt. Moreover, the disruption of these cellular events, either by the absence of beta-arrestin2 or by inhibiting the kinases, results in the inability of serotonin to induce the head twitch response in mice, which is a behavioral model of 5-HT2A receptor activation in the mouse frontal cortex. In contrast, DOI maintains its ability to internalize the 5-HT2A receptor in the absence of beta-arrestin2 and DOI, 5-MeO-DMT and N-methylserotonin do not activate beta-arrestin2-mediated signaling cascades in mouse embryonic fibrobalsts, primary cortical neurons or the mouse frontal cortex. The activation of the head twitch response by these hallucinogenic agonists is not disrupted in beta-arrestin2-knockout mice or in the presence of inhibitors to Akt. Collectively, these studies advance our understanding of the mechanism through which 5-HT2A receptor activation by different agonists can lead to distinct regulatory and signaling pathways in vivo. These studies suggest that agonist-directed 5-HT2A receptor regulation bifurcates based on interactions with beta-arrestin2. Moreover, the elucidation of these signaling pathways could have far reaching implications for the treatment of those neuropsychiatric disorders which have been associated with the disregulation of the 5-HT2A receptor.
Georgia Bishop, Ph.D (Advisor)
Laura Bohn, Ph.D (Advisor)
Candice Askwith, Ph.D (Committee Member)
Wolfgang Sadee, Dr.rer.nat. (Committee Member)
160 p.

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Citations

  • Schmid, C. L. (2011). Differential regulation of serotonin 2A receptor responsiveness by agonist-directed interactions with beta-arrestin2 [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1300287547

    APA Style (7th edition)

  • Schmid, Cullen. Differential regulation of serotonin 2A receptor responsiveness by agonist-directed interactions with beta-arrestin2. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1300287547.

    MLA Style (8th edition)

  • Schmid, Cullen. "Differential regulation of serotonin 2A receptor responsiveness by agonist-directed interactions with beta-arrestin2." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1300287547

    Chicago Manual of Style (17th edition)