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Hidden Complexity Seen in Serotonin Signaling

29 January 2008. Two recent papers out in PNAS focus on G protein-coupled serotonin receptors as targets for psychoactive drugs. Like other GPCRs, the serotonin receptors wire into multiple downstream signaling pathways, G protein-dependent and -independent. Which road they take depends on the cells in which they reside. Now, researchers are beginning to understand that the nature of the ligand can also influence the choice of signaling pathways. This concept is dramatically illustrated in work from Laura Bohn’s lab at Ohio State University College of Medicine, Columbus, Ohio, which reveals that serotonin (5-hydroxytryptamine, 5-HT) and a synthetic mimic act at the 5-HT2A receptor in vivo to trigger different signaling cascades. Although both ligands elicit the same behavioral response in mice, the effects of 5-HT require the β-arrestin-2 accessory protein, while the synthetic ligand uses a β-arrestin-independent pathway. The findings have major implications for drug discovery aimed at GPCRs: on the one hand, they suggest that all agonists are not created equal, and that current screening paradigms for GPCR agonists may misjudge their in vivo biological activities. On the other hand, the findings open up new possibilities for fine-tuning the specificity of GPCR agonists using ligands that target different signaling pathways.

The serotonin receptor is of interest in schizophrenia, where many atypical antipsychotic drugs antagonize the 5-HT2A receptor in addition to the dopamine D2 receptor. It has been proposed that these drugs’ actions include synergistic effects on the two systems. The second paper, from Karel Vales and Jan Bures of the Institute of Physiology at the Czech Academy of Science in Prague, carves out a possible role for the 5-HT2A/2C receptor subtypes in a specific action of antipsychotic drugs to improve cognitive symptoms in schizophrenia. They suggest that their work could explain why some antipsychotics appear more effective against cognitive symptoms of schizophrenia than others do.

A multitasking receptor
In the first paper, Bohn and coauthors Cullen Schmid and Kirsten Raehal set out to understand the signaling pathways behind the hallucinogenic effects of 5-HT2A agonists. (The receptor is the target for LSD, among other hallucinogens.) In particular, they wanted to find the role of β-arrestin, a scaffolding protein that associates with GPCRs and can modulate their responses to a ligand both positively and negatively. To do this, the investigators used a mouse model where 5-HT2A agonists cause a head twitch response to compare the action of serotonin with the synthetic hallucinogenic agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) in β-arrestin-2 knockout mice.

The core finding of the paper is that βARR2 knockout abolished the head twitch response to serotonin, but not to DOI, which surprisingly produced a similar head twitch in both wild-type and knockout mice. “These findings suggest that β-arrestin-2 mediates 5-HT-induced head twitches, whereas DOI produces this behavior in a β-arrestin-independent manner,” the authors write.

How can this happen? β-arrestins promote GPCR internalization, and the researchers found that the knockout mice show more receptors on the cell surface than in the cytoplasm relative to normal mice. In knockout mouse embryo fibroblasts, serotonin did not induce internalization of a transfected 5-HT2A receptor, while DOI did. Schmid and colleagues also looked at activation of the map kinase ERK, which is mediated by β-arrestin. Serotonin robustly activated ERK in wild-type cells, but to a much lower extent in knockouts. DOI activates EFK far less in wt cells, and the activation was barely affected by β-arrestin knockout. DOI activation of ERK went through phospholipase C rather than β-arrestin. These results held up in vivo, where the investigators showed that serotonin did not induce ERK activation in the frontal cortex of knockout mice, while DOI activated ERK in both wild-type and β-arrestin lacking mice.

“Schmid et al. present a compelling set of observations that can only be explicated by the emerging concept of functional selectivity,” write Atheir Abbas of Case Western Reserve University School of Medicine, Cleveland, Ohio, and Bryan Roth, University of North Carolina, Chapel Hill, in an accompanying perspective. The work exemplifies the emerging concept that cellular context is critical to determine the action of drugs at GPCRs, which are themselves conformational assemblages of receptor proteins and associated signaling molecules. “Given that ligands apparently induce differential patterns of signal transduction, it should be possible to design drugs that stabilize these unique conformational entities,” they write.

With a multiplicity of signaling events triggered by a single GPCR, drug developers might be able to pick and choose ligands that activate desired pathways while leaving others alone. “One can envision a scenario whereby drugs are identified via differential actions at a panel of functional readouts, yielding compounds with enhanced therapeutic efficiency and fewer side effects,” Abbas and Roth write.

The β-arrestins themselves can be drug targets, as shown in a recent study. That work demonstrated that lithium acts to disrupt a β-arrestin-2 signaling complex involving the Akt kinase (see SRF related news story). In the case of 5-HT2AR, Schmid and colleagues speculate that the receptor-arrestin association may set the tone for serotonin sensitivity. Therefore, modulating that interaction might be used to tweak the receptor response to endogenous serotonin or to pharmacological agents.

In the schizophrenia arena, clozapine and several other antipsychotics are 5-HT2AR antagonists, which leads Schmid et al. to conclude that their work “could have major implications in drug development for treating neuropsychiatric disorders such as depression and schizophrenia.” They note that clozapine induces 5-HT2AR internalization but not ERK activation in several systems, and speculate that clozapine may act by preventing downstream ERK1/2 activation, without preventing receptor internalization. The role of internalization versus ERK activation in determining the actions of clozapine remains to be determined.

Separating serotonergic and dopaminergic effects
The second paper directly addresses the action of antipsychotic drugs at 5-HT2A receptors, and proposes a link between that activity and improved cognitive symptoms in schizophrenia. Inhibition of 5-HT2A/2C receptors is thought to improve cognitive function, but the extent to which atypical antipsychotic drugs improve cognitive symptoms in patients is a matter of some debate (see SRF related news story). In their PNAS paper, first author Vera Bubenikova-Valesova of the Prague Psychiatric Center and colleagues studied the effects of three compounds in a rat model of memory impairment that they have developed to mimic the cognitive defects seen in schizophrenia. The model involves administration of the NMDA receptor antagonist MK-801 (dizocilpine), which produces psychosis and is proposed to be a model for schizophrenia, and testing of the rats in what the investigators call the active allothetic place avoidance task. The task puts rats on a rotating platform in which one quadrant delivers a mild electric shock. By using visual cues in the room, and ignoring irrelevant cues within the test arena, the rats learn to locate and avoid the shock area. The investigators believe performance in this test, with its competing stimuli, depends on a type of information processing disturbed in schizophrenia.

As previously shown by the same group, MK-801 treatment decreased the rats’ ability to avoid the shock part of the platform. The 5-HT2A/2C antagonist ritanserin blocked MK-801-induced cognitive impairment, while the dopamine D2 antagonist haloperidol did not. A mixed antagonist that hits both receptors—the atypical antipsychotic risperidone—also improved the rats’ cognitive performance. “Our results show that treatment with 5-HT2A/2C receptor antagonists, regardless of their activity at the D2 receptor, blocked the cognitive impairment induced by MK-810,” the authors conclude. Interestingly, in control rats (not treated with MK-801) the D2 blocker alone resulted in cognitive impairment, in agreement with previous studies. They did not see this effect with ritanserin, suggesting a specific effect of D2 receptor antagonism.

The results indicate that risperidone, an antipsychotic with high affinity for both the 5-HT2A/2C and D2 dopamine receptors, can give measurable cognitive improvement in this rat model of a schizophrenia cognitive deficit. The results agree with the idea that second-generation antipsychotics like clozapine treat a wider range of symptoms than specific D2 blockers like haloperidol because they affect the serotonergic system as well, although this has yet to be confirmed as a clinical benefit for any drug except clozapine (see SRF related news story). The model may be useful for testing the cognitive effects of other antipsychotic medications, the authors propose.—Pat McCaffrey.

Schmid CL, Raehal KM, Bohn LM. Agonist-directed signaling of the serotonin 2A receptor depends on {beta}-arrestin-2 interactions in vivo. Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):1079-84. Epub 2008 Jan 14. Abstract

Bubenikova-Valesova V, Stuchlik A, Svoboda J, Bures J, Vales K. Risperidone and ritanserin but not haloperidol block effect of dizocilpine on the active allothetic place avoidance task. Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):1061-6. Epub 2008 Jan 14. Abstract

Abbas A, Roth BL. Arresting serotonin. Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):831-2. Epub 2008 Jan 14. No abstract available. Abstract

Comments on News and Primary Papers
Comment by:  Patricia Estani
Submitted 23 February 2008 Posted 26 February 2008
  I recommend the Primary Papers

Comment by:  Atheir Abbas
Submitted 25 February 2008 Posted 27 February 2008
  I recommend the Primary Papers

Implicit in the findings of Schmid et al. is the idea that...  Read more

View all comments by Atheir Abbas
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