Candidate Review:

Role of the 5HT2c receptor in regulation ofmetabolism and mesolimbic dopamine

Richard O’Neil

Neuroscience Graduate Program, Vanderbilt University School of Medicine, U1205 Medical Center North, Nashville, TN 37232, USA.
Correspondence e-mail: richard.t.oneil@vanderbilt.edu

Abstract | Full Text | PDF

ABSTRACT |Serotonin (5HT) in the CNS plays an important role in regulation of behavioraland motivational states, and has an implied role in a number of behavioralpathologies including depression, schizophrenia, and drug abuse.  5HT acts inthe CNS by binding receptors on the surface of neurons which then facilitatemodulation of cellular processes and neuronal activity.  The 5HT2c receptoris a G-protein coupled receptor (GPCR) primarilyexpressed in the central nervous system.  The 5HT2c receptor is theonly known GPCR subject to a form of post transcriptional modification known asRNA editing, a process in which specific adenosine residues are converted toinosine resulting in functional recoding of the mRNA.  Editing of 5HT2c receptortranscripts alters the functional signaling characteristics of the receptor,thus modulating the role the receptor plays in various neural processes.  Thisreview discusses evidence for the role of the 5HT2c receptor inregulating feeding behavior, and mesoaccumbal dopamine signaling.  Furthermore,it addresses the possible implications of dynamic RNA editing in theseprocesses and discusses approaches to better understand the relationship betweenRNA editing and receptor function in vivo

A fundamental requirement for theevolution of complex nervous systems is the capacity for plasticity at themolecular level.  Enzymes, known as Adensosine Deaminases which Acton RNA (ADARs), have coevolved with nervous systems in many species tocatalyze hydrolytic deamination of specific adenosine residues on RNA sequences,resulting in functional alteration of RNA transcripts1.  In mammals,two genes have been shown to encode catalytically active ADARs (ADAR 1 and ADAR2), and both are expressed in most tissues but are highly enriched in the CNS2,3. Through their ability to convert adenosines to inosines at specific residues onprotein coding RNAs, ADARs have been shown to alter amino acid codons with profoundfunctional implications in a number of genes.  This recoding occurs becauseinosine is processed by the translational machinery as guanosine. This resultsin a functional coding alteration of A-to-G at edited residues1. Most of the characterized substrate RNAs modified by ADARs encode proteinsassociated with neuronal signaling.  These include voltage gated and ligandgated ion channels4,5, fast synaptic release machinery6,and at least one G-protein coupled neurotransmitter receptor; the 5HT2c receptor7.  The necessity of ADAR activity for viability and nervous system function hasbeen clearly demonstrated by a number of genetically modified mouse models inwhich activity of the respective ADARs or their editing activity on specificsubstrates has been disrupted8,9,10

RNA editing is a conservedmechanism allowing for precise and dynamic modulation of protein functionswithin the nervous system.  This unique process provides insight into thecritical aspects of protein function and makes it a powerful beacon to guidefurther scientific inquiry in molecular neuroscience. For example, thetranscript encoding the serotonin 2c receptor (5HT2c) can be editedat 5 adenosines in exon 5 of the mature mRNA. These sites are denoted A, B, E,C, and D sites respectively 5’ to 3’ (Figure 1c).  Considerabledifferences in signaling properties have been observed in vitro for anumber of the unique protein isoforms generated by different combinations ofediting at these 5 sites.  The functional differences result from modulation ofthree amino acid codons which genomically encodeisoleucine-asperigine-isoleucine respectively at residues 156-158-160 locatedwithin the second intracellular loop of the mature receptor.  Editing at theseamino acid codons allows for the production of 24 unique protein isoforms whichcan differ by as few as one or as many as three amino acids7 (Figure1).  The second intercellular loop of the receptor is known to be importantfor g-protein coupling and efficient activation of the Gq/11-phospholipase C beta (PLCβ) signaling cascade11-13Invitro evidence suggests that protein isoforms generated by differentcombinations of editing at these three amino acid codons have profoundlyaltered properties with respect to trafficking and signaling efficacy 7,14,15,18. Among the differences between edited isoforms is variability in ligandindependent signaling capacity, termed constitutive activity.  Constitutiveactivation of the 5HT2c receptor has been observed in multiple celllines transfected with transcripts encoding several different isoforms of thereceptor 14,16,18.  Importantly, this constitutive activity is notdetectable in cells expressing only the fully edited receptor isoform encodingvaline-glycine-valine (VGV) and the activity is significantly reduced inisoforms encoded by more edited transcripts VNV and VSV14.  Withrespect to ligand-dependant receptor activation, 5HT2c receptoragonists have reduced signaling efficacy and affinity for isoforms encoded bymore edited transcripts (Figure 1b).  This reduction in agonist efficacyhas been attributed to the existence of high and low affinity state receptors. According to the modified ternery complex model; receptors with constitutiveactivity fluctuate between inactive (R) and active (R*-G) conformations and thelevel of constitutive activity is a reflection of the relative time spent inR*-G state.  Agonist binding promotes formation of R*-G complex and theaffinity of an agonist is higher for the R*-G complex than for R.  The more editedisoforms are less likely to achieve the R*-G complex in absence of agonist andtherefore have reduced constitutive activity and exist predominately in a lowaffinity state16.  The existence of multiple affinity states issupported by experiments in which non-hydrolysable GTP analogs are used tofully uncouple g-proteins (G) from the R-G complex, resulting in only lowaffinity state receptors14,16.  The fact that all receptor isoformstested can achieve similar maximal activation of PI hydrolysis suggests thatthe ability of 5HT2c receptors to couple with g-proteins is not affectedby editing and that signaling efficacy is primarily altered by ligand affinityand constitutive receptor activation16.  While a great deal ofprogress has been made in characterizing the role of editing at this receptorfor signaling in vitro, the role of distinct isoforms in vivo is notunderstood.

The 5HT2c receptor has abroad expression profile in the CNS 17 and has been repeatedlyimplicated in the regulation of feeding behavior20 and rewardpathways19.  Based on the in vitro data, the expression ofdistinct 5HT2c receptor protein isoforms by RNA editing has thepotential to profoundly affect the role of the receptor in these systems.  Thisreview will focus on recent work illuminating the role of the 5HT2c receptorin the regulation of mesoaccumbal dopamine, as well as this receptor’s role inregulating feeding behavior.  Furthermore, it will discuss approaches to bettercharacterize the distribution of edited isoforms in various cell types andbrain regions.  Finally, it will outline efforts to test the hypothesis thatdynamic regulation of editing allows for precise modulation of behavior.

Figure 1 | 5HT2c isoforms. a | Proposed 7TM domain structure and amino acid sequence of the Serotonin 2c receptor amino acids subject to aleration by editing shown in colored spheres. b | Schematic representation summarizing the relationship between editing and signaling efficacy of respective receptor isoforms. c | Pre-mRNA sequence of edited region showing editing sites and assigned names designated for each site. Single letter codes for amino acids encoded by non-edited transcript shown in black; amino acids encoded after editing at each position are indicated in blue.

5HT2C RECEPTORS REGULATEMETABOLISM AND FEEDING BEHAVIOR IN MICE

Regulating metabolism and feedingbehavior is one of the most ubiquitous and fundamental functions facilitated bythe mammalian nervous system.  The brain maintains metabolic homeostasisthrough regulation of autonomic tone, glucose homeostasis, and by providing themotivational drive to consume food.  The notion that 5HT plays an importantrole in the regulation of feeding became evident in the early 1970’s when thedrug fenfluramine came on the market for weight loss.  The anorexigenic effectsof fenfluramine have been attributed to its ability to increase extracellular5HT levels20.  Recent studies by Vickers et al, in which knockoutmice lacking 5HT2c receptors are treated with fenflouramine,provided strong evidence that the 5HT2c receptor is primarilyresponsible for mediating the inhibition of feeding observed with fenfluraminetreatment.  It was observed that the anorexigenic efficacy of fenflouramine wasgreatly attenuated in these 5HT2c null animals21. Interestingly, phenotypic characterization of these mice lacking the 5HT2creceptor revealed that they are hyperphagic and develop adult onsetobesity22.  More recently, electrophysiological and moleculartechniques have allowed for a more precise characterization of the 5HT2c receptor’srole in feeding.  Heisler et al provide strong evidence thatpro-opiomelanocortin (POMC) neurons located within the arcuate nucleus of thehypothalamus express the 5HT2c receptor and that receptor activationpromotes excitability and α-MSH release23.  Accumulatingevidence implicating the 5HT2c receptor as a key component in theregulation of feeding behavior has made the receptor an attractive target fordevelopment of anti-obesity drugs20.

To understand the 5HT2c receptor’srole in physiology and attempt to develop informed pharmacologic interventionsit is imperative to consider the variable signaling properties observed amongdifferent receptor isoforms.  RNA editing of transcripts encoding 5HT2c receptorresults in production of receptor proteins with profound differences inconstitutive activity and 5HT mediated signaling efficacy.  Several labs havegenerated mice genetically modified to express only protein isoforms resultingfrom fully edited transcripts (VGV) or non-edited transcripts (INI) to studythe effects of these isoforms respectively in vivo.  Significantmetabolic alterations in the animals which only express the VGV receptorisoform suggest that the role of this receptor in regulating metabolism is morecomplicated that previously appreciated.  Specifically, these mice displayincreased basal metabolic rate which was found to be independent of themelanocortin- 4 receptor.   Consistent with the hypothesis that efficientexcitatory drive onto POMC neurons by the 5HT2c receptor is requiredfor normal inhibition of feeding, these mice display adult onset hyperphagiasimilar to that observed in the 5HT2c null animals24. Currently, it is not clear if this hyperphagia is directly related deficientactivation POMC neurons in the Arc, or an indirect feedback mechanism relatedthe enhanced basal metabolic rate.  Importantly, these results demonstrate apreviously unappreciated fundamental role for the 5HT2c receptor in regulatingmetabolic function.

Throughout evolution, animals have hadto cope with tremendous variations in food availability, across seasons andthrough generations, requiring the evolution of highly dynamic metabolicregulation.  Serotonin plays an important role in maintaining many aspects ofhomeostasis, but the specific role that RNA editing plays in these processes isnot known.  Interestingly, it has been observed that prenatal dietarydeficiencies can lead to altered brain serotonin homeostasis25,metabolic disfunction, and reduced sensitivity to d-fenflouramine26. Specifically, Lopez de Souza et al observed significant reductions ind-fenfluramine-induced suppression of feeding and arcuate c-fos activation inrats exposed to perinatal protein deficiency.  The levels of 5HT2creceptor transcripts are unchanged in these animals suggesting that a mechanismdownstream of receptor expression is responsible for this lack of sensitivity26. The RNA-editing profile for the 5HT2c receptor has not beencharacterized in these rats, but alterations in editing have the potential tocontribute to the findings observed in these studies.   Characterizationof RNA-editing dynamics in POMC neurons during normal development and inresponse to prenatal malnutrition may elucidate the relationship betweenmetabolic disfunction and 5HT2c receptor function.

5HT2C RECEPTORS REGULATEMESOLIMBIC DOPAMINE SIGNALING

Animals possess the unique ability tophysically interact with their environment in order to promote their ownsurvival and reproduction.  Goal directed behavior and adaptive learning haveevolved in higher vertebrates to facilitate this need to efficiently respond tothe nearly infinite possible circumstances an animal may find itself in. Mechanistically, goal directed behavior and adaptive learning requires; goalidentification, perception of relevant sensory stimuli, generation of possiblemotor sequences, and anticipation of the relative utility of particular motorsequences in attaining the goal.  Furthermore, the ability to encode rewardupon the execution of effective motor sequences allows animals to modify andperfect behavioral sequences to efficiently achieve goals.  The mesolimbicsystem, which includes; the Nucleus Accumbens (NAc), olfactory tubercle, ventralpallidum (VP), mediodorsal thalamus, ventral tegmental area, lateralhypothalamus, limbic cortex, and amygdala provides the neural substrate forreward associated learning and motivated behavior27.  Dopamine (DA)release in the NAc and olfactory tubercle is thought to be a key component ingoal directed selection of motor programs and underlie the neural coding ofreward28.  Dopamine is supplied to the ventral striatum primarily bygroups of neurons located in the midbrain known collectively as the ventraltegmental area (VTA), and its release in the medial shell of the NAc and medialolfactory tubercle directly correlates with the rewarding effects of achievinggoals as well as the reinforcing effects of drugs of abuse28.

5HT is supplied to the structures ofthe mesolimbic system by neurons in the dorsal raphe and plays a significantrole in the regulation of NAc DA release33 and 5HT2c receptortranscripts can be detected by in situ hybridization the VTA and throughout theNAc17.  Studies in which selective 5HT2c receptoragonists, antagonists, and inverse agonists are administered while monitoringDA levels in NAc via microdialysis suggest that activation of 5HT2c receptorshave a net inhibitory effect on both baseline and drug induced DA release inthe ventral striatum.  Navailles et al showed that intra-accumbal infusion ofinverse agonist SB 206553, but not antagonist SB 242084, increased basal DAefflux in the NAc.  They also showed that the acute decrease in basal accumbalDA levels elicited by systemic infusion of agonist Ro 60-0175 was attenuated byintra VTA infusion of antagonist SB 24208439.  Taken together, theseresults suggest that phasic activation of receptors in the VTA attenuates DArelease and constitutive activity of receptors in the NAc provide tonicsuppression of DA release.  Further supporting an inhibitory role for 5HT2creceptors with respect to DA release, Gobert et al showed that systemicadministration of inverse agonist and agonist dose dependently increased anddecreased respectively, the firing rate of DAergic neurons in the VTA33. Activation of 5HT2c receptors has been shown to excite cells viaactivation of PLC and subsequent modulation of ion channel activity29,30. These observations have lead to the hypothesis that 5HT2c receptorsin the NAc and VTA negatively regulate DA release by DAergic neurons byactivating inhibitory GABAergic interneurons which, in turn, directly inhibitDAergic neuron activity.  In agreement with this hypothesis, immunoreactivityhas been observed primarily in GABAergic cell bodies in the VTA and NAc asimplied by co-staining of cells with antibodies against glutamate decarboxylasethe enzyme that synthesizes GABA from glutamate31, 32.   

Recently, several studies haveattempted to evaluate the effects of various serotonin receptor ligands on theacquisition of stimulant addiction and on reinstatement of drug seekingbehavior after extinction.  The inhibitory role of 5HT2c receptoragonists on DA release has lead to the hypothesis that such drugs could beeffective in treating addiction.  Indeed, several studies have indicated thatsystemic administration of agonists decreases the acute hyperlocamotiveresponse to stimulants and reduces self-administration and reinstatement ofcocaine seeking bahavior34.  As noted above, investigation into theregulation of DA by 5HT2c receptors has indicated that severaldistinct populations of receptors exist each with different functional roles inregulation of DA19, 34.  All of the subcortical 5HT2creceptor populations analyzed to date seem to provide a net inhibitory drive onNAc DA release, but the differential responses to inverse agonists,antagonists, and agonists suggests that the receptors play distinct roles inresponding to 5HT.  Functional differences of 5HT populations merit furtherinvestigation; it is possible that select cell types express different editedisoforms with variable levels of constitutive activity and provide tonic orphasic control of DA release respectively.

CONCLUSIONS

A number of studies have attempted toprofile the distribution of 5HT2c receptor edited isofoms in thebrains regions of humans who had suffered from neuro-pathologies, particularlydepression and schizophrenia35,36.  One study by Gurevich et alreported that changes in editing observed in pre-frontal cortex of suicidevictims was the opposite (at each respective editing site) of the changes thatcould be induced by treating mice with the SSRI fluoxetine36.  Theauthors suggested not only that altered editing may contribute to pathology inhumans, but also that editing could be manipulated by pharmacologicintervention affecting 5HT tone.  Following these findings, effort was spentattempting to elucidate how sustained alterations in 5HT tone via pharmacologicintervention might affect editing of 5HT2c receptor transcripts. Englander and Gurevich subsequently provided evidence for dynamic modulation ofRNA editing by a number of factors including stress37, 5HT depletion38,and SSRI treatment36,37.  The possibility that RNA editing can bedynamically modulated in a substrate specific manner carries compellingimplications with respect to normal and pathologic brain function.  While therelationship between RNA editing dynamics, drug treatment, and behavioralpathology is not understood, it is an important phenomenon to consider whenstudying CNS function. 

Accumulating evidence implies that the5HT2c receptor is a key component in the transduction of 5HT’s signal in the CNS.  Thisreview discussed receptor function in two key systems which regulatefundamental aspects of behavior; hypothalamic regulation of metabolism, and DAregulation in the ventral striatum.  In addition to being medically relevantbehavioral systems, these circuits are relatively well characterized, havereadily observable outputs, and several well established experimentalparadigms.  With the recent development of tools such as knock-in miceexpressing only specific edited isoforms of the receptor, and selectiveligands, it will be possible to begin understanding the role of thisneurotransmitter receptor’s unique and complex molecular biology.  Serotoninrelated drug intervention is at the forefront of the struggle to treat a widearray of psychiatric disorders.  To develop informed therapies based onmodulation of serotonin signaling it is imperative to understand the roleplayed by this prominent monoamine receptor.

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This study showed that serotonin 2c receptors on POMC neurons in the arcuate nucleus play an important role in the hypothalamic regulation of feeding behavior. 

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36. Gurevich I, Hadassah T, Arango V, Dwork A, Mann JJ, Schmauss C (2002).  Altered Editingof Serotonin 2C Receptor Pre-mRNA in the Prefrontal Cortex of Depressed SuicideVictims.  Neuron. 34: 349-356.

This paper provides evidence that altered editing contributes to suicidal depression and that SSRI treatmentcan result in reversal of these alterations.

37. EnglanderMT, Dulawa SC, Bhansali P, Schmauss C (2005).  How stress and fluoxetinemodulate serotonin 2c receptor pre-mRNA editing.  J. Neuroscience. 25(3): 648-651.

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39. Navailles S, Moison D, Ryczko D, Spampinato U (2006).  Region-dependantregulation of mesoaccumbens dopamine neurons in vivo by the constitutiveactivity of central serotonin 2c receptors.  Journal of Neurochemistry99: 1311-1319.

This study provides evidencefor the roles of different populations of receptors in distinct brain regionsregulating NAc dopamine release.

FURTHER INFORMATION

Ron Emeson’s Lab