Serotonin receptor 2
Among immortalized teratocarcinoma-derived cells, the clone 1C11 is a committed precursor of the neuronal lineage. On day 2 of its serotoninergic differentiation, this clone expresses only one subtype of serotonin [5-hydroxytryptamine (5-HT)] receptor, which is functionally coupled to phosphatidylinositol hydrolysis. The identity of these receptors was established by comparing their properties with those of 5-HT2B receptors expressed by LMTK- fibroblasts stably transfected with the recently cloned murine cDNA NP75 (LM5 cells). In both cell types, the analysis agonist (125I-DOI) binding reveals the presence of a single class of sites; the affinity of these sites for agonist is one order of magnitude lower than that reported for 5-HT2A receptors. In 1C11 cells differentiated for 2 days, as well as in LM5 cells, DOI binding is decreased by nonhydrolyzable analogs of GTP, indicating that the 5-HT2B receptor is functionally coupled to a G protein. The DOI-induced increase of phosphoinositide hydrolysis, which is correlated with both GTPase activity and binding data, is mediated by a Gq protein. This work demonstrates that the 5-HT2B receptor is functionally expressed before complete serotoninergic differentiation of 1C11 cells. The inducible 1C11 clone thus provides an in vitro model to investigate the possible role of the 5-HT2B receptor in the expression of the serotoninergic phenotype (Loric, 1995).
The study of signaling cascades and of functional interactions between 5-hydroxytryptamine (5-HT) receptor pathways with heterogenous brain cell populations remains an arduous task. A serotonergic cell line was used to elucidate cross-talk between 5-HT receptors and to demonstrate the involvement of two 5-HT2 receptor subtypes in the regulation of 5-HT1B/1D function. The inducible 1C11 cell line has the unique property of acquiring within 4 days a complete serotonergic phenotype (1C11* cells), including three 5-HT receptors. 5-HT1B/1D and 5-HT2B receptors are expressed from day 2 of the serotonergic differentiation, while 5-HT2A receptors are induced at day 4. 5-HT2B receptors are coupled with the phospholipase A2 (PLA2)-mediated release of arachidonic acid (AA) and the activation of 5-HT2B receptors in 1C11*d2 cells inhibits the 5-HT1B/1D receptor function via a cyclooxygenase-dependent AA metabolite. At day 4, this 5-HT2B-mediated inhibition of the 5-HT1B/1D function can be blocked upon concomitant 5-HT2A activation, although a 5-HT2A/PLA2 positive coupling is evident. This suggests the existence in 1C11*d4 cells of pathway(s) for 5-HT2A receptors, distinct from PLC and PLA2. Finally, this study reveals the antagonistic roles of 5-HT2A and 5-HT2B receptors in regulating the function of 5-HT1B/1D, a receptor involved in neuropsychiatric disorders and migraine pathogenesis (Tournois, 1998).
The 5-Hydroxytryptamine (5-HT)2C receptor (originally known as the 5-HT1C receptor) is a member of the 5-HT2 subfamily of G protein coupled receptors, which is known to couple to phospholipase C. Within the 5-HT2 subfamily, only the 5-HT2C receptor also couples to inhibition of forskolin-stimulated cAMP production when expressed at high density in stably transformed AV12 cells. The 5-HT2C receptor couples with high efficacy to both phospholipase C as measured by IP3 (inositol 1,4,5-trisphosphate) production and to inhibition of forskolin-stimulated cAMP production. The 5-HT2A and 5-HT2B receptors, while coupling to phospholipase C with high affinity (EC50s of 19.24 nM +/- 6.44 and 1.24 nM +/- 0.136 respectively), do not decrease adenylyl cyclase activity. The 5-HT2C receptor actions in both systems show the expected pharmacology for the 5-HT2C receptor, e.g., mesulergine antagonizes the effects of 5-HT and spiperone does not. Preincubation of cells with PTX shows that the G protein coupling of the 5-HT2C receptor to phospholipase C is PTX insensitive, while the G protein coupling to inhibition of adenylyl cyclase is PTX sensitive, even with concentrations as low as 20 ng/ml of PTX. PTX pretreatment of the 5-HT2C bearing cells also unmasks a small stimulatory effect on adenylyl cyclase. When expressed at low density the 5-HT2C receptor potentiates forskolin-stimulated cAMP production by 2 fold while still maintaining its ability to enhance PI hydrolysis. A more modest potentiation of cAMP production is noted with low density expression of the 5-HT2B receptor. Thus the ability of the 5-HT2C receptor to interact with several effectors through at least two different G proteins is, in part, receptor subtype specific but also influenced by receptor density (Lucaites, 1996).
A variety of receptors coupled to GTP-binding regulatory proteins (G proteins) initiate signals that culminate in activation of the mitogen-activated protein kinases ERK1 and ERK2. Similarly, the human 5-HT1A receptor expressed in Chinese hamster ovary cells promotes activation of ERK1 and ERK2, but the pathway used does not conform entirely to those proposed previously for G protein-coupled receptors. Activation of ERK2 by the 5-HT1A receptor-selective agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT) is inhibited completely by pertussis toxin and substantially by prolonged treatment of cells with phorbol 12-myristate 13-acetate. However, the implied requirement for protein kinase C is negated in studies with bisindolylmaleimide and Ro-31-8220, which, although completely inhibiting activation of ERK2 by phorbol ester, has no impact on activation by 8-OH-DPAT. Moreover, the anticipated inhibition by the tyrosine kinase inhibitors genistein and herbimycin A is marginal at best. As expected for a Gi-coupled receptor, the inhibitors of phosphatidylinositol 3-kinase wortmannin and LY294002 inhibit activation of ERK2, albeit only partly (70%). Of significance, an inhibitor of a phosphatidylcholine-specific phospholipase C, tricyclodecan-9-yl-xanthogenate (D609), causes a similar degree of inhibition. When the two types of inhibitors are combined, an almost complete inhibition is achieved. These data suggest that phosphatidylinositol 3-kinase and phosphatidylcholine-specific phospholipase C represent components of different, but partly overlapping pathways that can account almost entirely for the activation of ERK2 by the 5-HT1A receptor (Cowen, 1996).
Chinese hamster ovary cells (CHO-K1) express an endogenous 5-hydroxytryptamine (5-HT)1B-like receptor that is negatively coupled to adenylyl cyclase through a pertussis toxin (PTX)-sensitive mechanism. Furthermore, the human adenosine A1 receptor, when expressed in CHO-K1 cells (CHO-A1), has been shown to mobilize intracellular Ca2+ through a PTX-sensitive mechanism. Therefore the aim of this investigation was to determine whether the endogenous 5-HT1B-like receptor is able to stimulate increases in intracellular free [Ca2+] ([Ca2+]i) in CHO-A1 cells. In agreement with previous studies using CHO cells, 5-hydroxytryptamine (5-HT) elicited a concentration-dependent inhibition of forskolin-stimulated [3H]-cyclic AMP production in CHO-A1 cells. 5-HT inhibits about half of the [3H]-cyclic AMP accumulation induced by 3 microM forskolin. Forskolin stimulated [3H]-cyclic AMP accumulation is also inhibited by 5-HT1 receptor agonists. 5-HT elicits a concentration-dependent increase in [Ca2+]i in CHO-A1 cells. In the presence of 2 mM extracellular Ca2+, 5-HT more than doubles [Ca2+]i. These data demonstrate that in CHO-K1 cells the endogenously expressed 5-HT1B-like receptor couples to the phospholipase C/Ca2+ signaling pathway through a PTX-sensitive pathway, suggesting the involvement of Gi/Go protein(s) (Dickenson, 1996).
Alzheimer's disease amyloid consists of amyloid beta-peptides (Abeta) derived from the larger precursor amyloid precursor protein (APP). Non-amyloidogenic APP processing involves regulated cleavage within the Abeta domain followed by secretion of the ectodomain (APPs). APPs secretion can be stimulated by muscarinic acetylcholine receptors coupled to phospholipases and kinases. To determine whether other receptor classes can regulate APP processing, the relation between serotonin receptors and APPs secretion was examined. Serotonin increases APPs release 3-4-fold in 3T3 cells that stably overexpress either 5-HT2aR or 5-HT2cR. The increase is dose-dependent and is blocked by serotoninergic antagonists. Phorbol esters also increase APPs secretion, but neither kinase inhibitors nor down-regulation of PKC block the serotonin-induced increase in APPs secretion. Thus PKC is not necessary to stimulate APPs secretion. Phospholipase A2 (PLA2) inhibitors block the 5-HT2aR-mediated increase in APPs secretion, suggesting a role for PLA2 in coupling 5-HT2aR to APP processing. In contrast, coupling of 5-HT2cR to APPs secretion involves both PKC and PLA2. Serotonin also stimulates the release of the APLP2 ectodomain, suggesting that additional members of the APP multigene family are processed via similar regulated pathways. Inasmuch as generation of APPs precludes the formation of amyloidogenic derivatives, serotonin receptors provide a novel pharmacological target to reduce these derivatives in Alzheimer's disease (Nitsch, 1996).
Serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A and 5-HT2C receptors belong to the class of phosphoinositide-specific phospholipase C (PLC)-linked receptors. Conditions were established for measuring 5-HT2A-linked and 5-HT2C-linked PLC activity in membranes prepared from previously frozen rat frontal cortex and caudate. In the presence of Ca2+ (300 nM) and GTPgammaS (1 microM), 5-HT increases PLC activity in caudate membranes. Pharmacological analysis using the selective 5-HT2A antagonist (spiperone), and the nonselective 5-HT(2A/2C) antagonist (mianserin), demonstrates that over half of the 5-HT-stimulated PLC activity is due to stimulation of 5-HT2C receptors as opposed to 5-HT2A receptors. Radioligand binding assays with [3H]RP 62203 and [3H]mesulergine were used to quantify 5-HT2A and 5-HT2C sites, respectively, in caudate. In contrast to activity in caudate, PLC activity in frontal cortex is stimulated by 5-HT in a manner that is inhibited by the 5-HT2A-selective antagonists: spiperone and ketanserin. Taken together, the results indicate that 5-HT2A- and 5-HT2C-linked PLC activity can be discerned in brain regions possessing both receptor subtypes using membranes prepared from previously frozen tissue. More importantly, significant 5-HT2C-mediated phosphoinositide hydrolysis is observed in caudate, despite the relatively low density of 5-HT2C sites. The significance of these observations with respect to the physiological function of 5-HT2C receptors is discussed (Wolf, 1997).
To investigate the receptor-channel coupling pathway, the coding region of the 5-HT1a receptor was subcloned into two plasmid vectors pSP64(polyA+) and pSP64T. Compared to the original 5-HT1a receptor construct G-21, both new constructs greatly increase the expression of functional 5-HT1a receptors in Xenopus oocytes, which develop large inward current responses to 5-HT. These responses are dose-dependent (EC50 approximately 150 nM), and can be elicited also by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The 5-HT1a receptor mediated current has an oscillatory time course, and a reversal potential close to the equilibrium potential for Cl- (ca. -25 mV). Moreover, during and for some minutes following the application of 5-HT, these oocytes acquire the property of generating a transient inward current when their membrane is hyperpolarized. These features are characteristic of responses mediated by other receptors (e.g. muscarinic, angiotensin, serum receptors, etc.) that are known to couple to the endogenous PLC/PI second messenger pathway in Xenopus oocytes. In particular, the 5-HT1a receptor mediated current is very similar to the current induced by 5-HT-stimulation of heterogenic 5-HT2c receptors. These results show further that the 5-HT1a receptor couples to the endogenous PLC/PI pathway much less efficiently than the 5-HT2c receptor. These results demonstrate clearly that the human 5-HT1a receptor can couple efficiently to the Xenopus oocyte endogenous PLC/PI pathway, and provide additional evidence for cell-specific signal transduction (Ni, 1997).
There are many examples of a single receptor coupling directly to more than one cellular signal transduction pathway. Although traditional receptor theory allows for activation of multiple cellular effectors by agonists, it predicts that the relative degree of activation of each effector pathway by an agonist (relative efficacy) must be the same. Agonists at the human serotonin2A (5-HT2A) and 5-HT2C receptors activate differentially two signal transduction pathways independently coupled to the receptors [phospholipase C (PLC)-mediated inositol phosphate (IP) accumulation and phospholipase A2 (PLA2)-mediated arachidonic acid (AA) release]. The relative efficacies of agonists differ depending on which signal transduction pathway is measured. Moreover, relative to 5-HT, some 5-HT2C agonists (e.g., 3-trifluoromethylphenyl-piperazine) preferentially activate the PLC-IP pathway, whereas others (e.g., lysergic acid diethylamide) favor the PLA2-AA pathway. In contrast, when two dependent responses are measured (IP accumulation and calcium mobilization), agonist relative efficacies are not different. These data strongly support the hypothesis termed 'agonist-directed trafficking of receptor stimulus'. Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of receptor activation, suggesting that two active receptor states may be sufficient to explain pathway-dependent agonist efficacy. Rational drug design that optimizes preferential effector activity within a group of receptor-selective drugs holds the promise of increased selectivity in clinically useful agents (Berg, 1998a).
There is now considerable evidence that a single receptor subtype can couple to multiple effector pathways within a cell. The concept termed 'agonist-directed trafficking of receptor stimulus' suggests that agonists may be able to selectively activate a subset of multiple signaling pathways coupled to a single receptor subtype. 5-HT2A and 5-HT2C receptors couple to phospholipase C-(PLC) mediated inositol phosphate (IP) accumulation and PLA2-mediated arachidonic acid (AA) release. Relative efficacies of agonists (referenced to 5-HT) differ depending on whether IP accumulation or AA release is measured. For the 5-HT2C receptor system, some agonists (e.g. TFMPP) preferentially activate the PLC-IP pathway, whereas others (e.g. LSD) favored PLA2-AA. As expected, the EC50s of agonists do not differ between pathways. For the 5-HT2A receptor system, all agonists tested had greater relative efficacy for PLA2-AA than for PLC-IP. In contrast, relative efficacies were not different for 5-HT2A agonists when sequential effects in a pathway were measured (IP accumulation vs. calcium mobilization). These data strongly support the agonist-directed trafficking hypothesis (Berg, 1998b).
Mechanisms underlying the 5-HT2A receptor induction of intracellular Ca2+ mobilization and Ca2+ influx in type I astroglial cells in primary culture from newborn rat cerebral cortex were evaluated. The 5-HT-evoked Ca(2+)-transients, inhibited by the 5-HT2A antagonists ketanserin or 4-(4-fluorobenzoyl)-1-(4-phenylbutyl) piperidine oxalate, consist of an initial peak caused by inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release from internal stores, and a second sustained part which was due to Ca2+ transport over the plasma membrane. The responses are pertussis toxin-insensitive, suppressed by the phospholipase C inhibitor neomycin and were inhibited by the Ca(2+)-ATPase inhibitor thapsigargin. Furthermore, the responses are inhibited by the IP3 receptor antagonist heparin. When the second sustained part of the 5-HT-evoked response was studied, it was concluded that Ca2+ influx is not a result of opening of voltage operated calcium channels of either L, N or T-type. Instead it appeared that Ca2+ enters the cells through specialized voltage independent Ca2+ channels, which are dependent on IP3 production and subsequent Ca2+ release from internal stores. From this, it is concluded that 5-HT opens Ca2+ channels in astrocytes that closely resemble depletion-operated Ca2+ channels (DOCCs) (Hagberg, 1998).
Signaling pathways responsible for serotonin (5-HT)-mediated induction of early response genes prostaglandin G/H synthase-2 (PGHS-2, cyclooxygenase-2) and egr-1 were investigated in rat mesangial cells. Gene induction by 5-HT is dependent on 5-HT2A receptors that are pertussis toxin insensitive, which indicates coupling to a G-protein of the Gq family. Binding of 5-HT to this receptor activates phosphatidylinositol-specific phospholipase C (PLC) and release of Ca2+ from internal stores, but this activation is not related to PGHS-2 mRNA expression. Similarly, PI-3 kinase is not involved in 5-HT signaling. Instead, inhibition of phosphatidylcholine-specific PLC interfers with PGHS-2 and egr-1 mRNA induction, suggesting this enzyme is a link between 5-HT2A receptors and protein kinase C, an essential part of 5-HT-mediated signaling. The MAP kinase pathway has been identified as common signaling pathway of 5-HT or phorbol ester-induced gene expression. Increase of intracellular cAMP by forskolin or dibutyryl cAMP does not induce PGHS-2 or egr-1 mRNA expression by itself, but strongly inhibits 5-HT-mediated mRNA induction. PGHS-2 mRNA and protein induction by 5-HT is also abolished by chelation of Ca2+ ions by EGTA, suggesting involvement of Ca2+-dependent enzymes. In contrast, egr-1 mRNA expression is superinduced in the presence of EGTA. Induction of Egr-1 protein is not changed by EGTA; this hints at possible Ca2+ sensitive posttranscriptional steps. Activation of the Gq-coupled 5-HT2A receptor thus leads to the expression of the early response genes PGHS-2 and egr-1, using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells, respectively (Goppelt-Struebe, 1998).
The action of 5-hydroxytryptamine (5-HT) via the 5-HT1A receptor on dissociated rat dorsal raphe neurons was characterized under the whole-cell mode by using the nystatin-perforated patch-clamp technique. Under voltage-clamp conditions, 5-HT induces an inwardly rectifying K+ current (I5-HT) in a concentration-dependent manner. I5-HT is mimicked by 5-HT1A receptor agonists. I5-HT is reversibly blocked by such 5-HT1A receptor antagonists. I5-HT is antagonized in a concentration-dependent manner by such K+ channel blockers as quinine, Ba2+ and 4-aminopyridine but is relatively insensitive to both CS+ and tetraethylammonium. When the neurons are loaded with guanosine 5'-O-3-thiotriphosphate through a patch pipette, the K+ current induced by 5-HT becomes irreversible. N-ethylmaleimide (NEM), a sulfhydryl alkylating agent, irreversibly blocks I5-HT. The intracellular perfusion with a Ca2+ chelator, or neomycine (a phospholipase C inhibitor), does not significantly affect the 5-HT-induced response. A protein kinase C (PKC) activator has only a weak inhibitory effect on I5-HT, and a PKC inhibitor fails to significantly occlude I5-HT. Therefore, the K+ conductance activated via the 5-HT1a receptor of dorsal raphe neurons is thus characterized by the sensitivity to such K+ channel blockers as quinine, Ba2+ and 4-aminopyridine. Moreover, a G protein that is NEM-sensitive and can couple to the 5-HT1A receptor, is thus considered to activate the inwardly rectifying K+ conductance without being mediated by such second messengers as Ca2+ and PKC (Katayama, 1997).
The neurotransmitter serotonin mediates a wide variety of peripheral and central physiological effects through the binding to multiple receptor subtypes. Among them, serotonin 5-HT2A receptors are known to activate the phospholipase C-beta second messenger pathway. In rat skeletal muscle myoblasts a functional serotonin 5-HT2A receptor has been identified and localized. This receptor is detected on the plasma membrane, in myoblasts, and at the level of T-tubules in contracting myotubes. Binding of serotonin to its receptor increases the expression of genes involved in myogenic differentiation. Unexpectedly, the 5-HT2A receptor is able to activate another signaling pathway; it triggers a rapid and transient tyrosine phosphorylation of Jak2 kinase in response to serotonin. Jak2 auto-phosphorylation is followed by the tyrosine phosphorylation of STAT3 (signal transducers and activators of transcription) and its translocation into the nucleus. The 5-HT2A receptor and STAT3 co-precipitate with Jak2, indicating that they are physically associated. It is concluded that the serotonin 5-HT2A receptor identified in skeletal muscle myoblasts is able to activate the intracellular phosphorylation pathway used by cytokines. The presence of serotonin receptors in T-tubules suggests a role for serotonin in excitation-contraction coupling and/or as an effectof skeletal muscle fiber repair (Guillet-Deniau, 1997).
G protein-coupled receptors (GPCRs) are essential for normal central CNS function and represent the proximal site(s) of action for most neurotransmitters and many therapeutic drugs, including typical and atypical antipsychotic drugs. Similarly, protein kinases mediate many of the downstream actions for both ionotropic and metabotropic receptors. Genetic deletion of p90 ribosomal S6 kinase 2 (RSK2; see Drosophila RSK) potentiates GPCR signaling. Initial studies of 5-hydroxytryptamine (5-HT)2A receptor signaling in fibroblasts obtained from RSK2 wild-type (+/+) and knockout (-/-) mice showed that 5-HT2A receptor-mediated phosphoinositide hydrolysis and both basal and 5-HT-stimulated extracellular signal-regulated kinase 1/2 phosphorylation are augmented in RSK2 knockout fibroblasts. Endogenous signaling by other GPCRs, including P2Y-purinergic, PAR-1-thrombinergic, beta1-adrenergic, and bradykinin-B receptors, was also potentiated in RSK2-deficient fibroblasts. Importantly, reintroduction of RSK2 into RSK2-/- fibroblasts normalized signaling, thus demonstrating that RSK2 apparently modulates GPCR signaling by exerting a 'tonic brake' on GPCR signal transduction. These results imply the existence of a novel pathway regulating GPCR signaling, modulated by downstream members of the extracellular signal-related kinase/mitogen-activated protein kinase cascade. The loss of RSK2 activity in humans leads to Coffin-Lowry syndrome, which is manifested by mental retardation, growth deficits, skeletal deformations, and psychosis. Because RSK2-inactivating mutations in humans lead to Coffin-Lowry syndrome, these results imply that alterations in GPCR signaling may account for some of its clinical manifestations (Sheffler, 2006).
In mammals, the environmental light/dark cycle strongly synchronizes the circadian clock within the suprachiasmatic nuclei (SCN) to 24 hr. It is well known that not only photic but also nonphotic stimuli can entrain the SCN clock. Actually, many studies have shown that a daytime injection of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH DPAT), a serotonin 1A/7 receptor agonist, as a nonphotic stimulus induces phase advances in hamster behavioral circadian rhythms in vivo, as well as the neuron activity rhythm of the SCN in vitro. Recent reports suggest that mammalian homologs of the Drosophila clock protein Period are involved in photic entrainment. Therefore, an examination was made to determine whether phase advances elicited by 8-OH DPAT are associated with a change of Period mRNA levels in the SCN. In this experiment, partial cDNAs were cloned encoding hamster Per1, Per2, and Per3 and both circadian oscillation and the light responsiveness of Period were observed. The inhibitory effect of 8-OH DPAT on hamster Per1 and Per2 mRNA levels in the SCN occurs only during the hamster's mid-subjective day, but not during the early subjective day or subjective night. The present findings demonstrate that the acute and circadian time-dependent reduction of Per1 and/or Per2 mRNA in the hamster SCN by 8-OH DPAT is strongly correlated with the phase resetting in response to 8-OH DPAT (Horikawa, 2000).
Exposure to UV radiation induces skin cancer and suppresses the immune response. To induce immune suppression, the electromagnetic energy of UV radiation must be absorbed by an epidermal photoreceptor and converted into a biologically recognizable signal. Two photoreceptors have been recognized: DNA and trans-urocanic acid (UCA). Trans-UCA is normally found in the outermost layer of skin and isomerizes to the cis isomer upon exposure to UV radiation. Although UCA was identified as a UV photoreceptor years ago, and many have documented its ability to induce immune suppression, its exact mode of action remains elusive. Particularly vexing has been the identity of the molecular pathway by which cis-UCA mediates immune suppression. This study provides evidence that cis-UCA binds to the serotonin [5-hydroxytryptamine (5-HT)] receptor with relatively high affinity (Kd = 4.6 nM). Anti-cis-UCA antibody precipitates radiolabeled 5-HT, and the binding is inhibited by excess 5-HT and/or excess cis-UCA. Similarly, anti-5-HT antibody precipitates radiolabeled cis-UCA, and the binding is inhibited by excess 5-HT or excess cis-UCA. Calcium mobilization is activated when a mouse fibroblast line, stably transfected with the human 5-HT2A receptor, is treated with cis-UCA. Cis-UCA-induced calcium mobilization os blocked with a selective 5-HT2A receptor antagonist. UV- and cis-UCA-induced immune suppression is blocked by antiserotonin antibodies or by treating the mice with 5-HT2A receptor antagonists. These findings identify cis-UCA as a serotonin receptor ligand and indicate that the immunosuppressive effects of cis-UCA and UV radiation are mediated by activation of the 5-HT2A receptor (Walterscheid, 2006).
Serotonin neurotransmission in the central nervous system modulates depression and anxiety-related behaviors in humans and rodents, but the responsible downstream receptors remain poorly understood. Global disruption of 5-HT2A receptor (5HT2AR) signaling in mice reduces inhibition in conflict anxiety paradigms without affecting fear-conditioned and depression-related behaviors. Selective restoration of 5HT2AR signaling to the cortex normalizes conflict anxiety behaviors. These findings indicate a specific role for cortical 5HT2AR function in the modulation of conflict anxiety, consistent with models of cortical, 'top-down' influences on risk assessment (Weisstaub, 2006).
An function for 5-HT2B receptors in central nervous system has not yet been clearly elucidated. The role of different 5-HT(2) receptor subtypes has been studied in the medullary breathing center, the pre-Botzinger complex, and on hypoglossal motoneurons in rhythmically active transversal slice preparations of neonatal rats and mice. Local microinjection of 5-HT(2) receptor agonists revealed tonic excitation of hypoglossal motoneurons. Excitatory effects of the 5-HT2B receptor agonist BW723C86 could be blocked by bath application of LY272015, a highly selective 5-HT2B receptor antagonist. Excitatory effects of the 5-HT(2A/B/C) receptor agonist alpha-methyl 5-HT could be blocked by the preferential 5-HT2A receptor antagonist ketanserin. Therefore, 5-HT-induced excitation of hypoglossal motoneurons is mediated by convergent activation of 5-HT2A and 5-HT2B receptors. Local microinjection of BW723C86 in the pre-Botzinger complex increased respiratory frequency. Bath application of LY272015 blocked respiratory activity, whereas ketanserin had no effect. Therefore, endogenous 5-HT appears to support tonic action on respiratory rhythm generation via 5-HT2B receptors. In preparations of 5-HT2B receptor-deficient mice, respiratory activity appeared unaltered. Whereas BW723C86 and LY272015 had no effects, bath application of ketanserin disturbed and blocked rhythmic activity. This demonstrates a stimulatory role of endogenous 5-HT2B receptor activation at the pre-Botzinger complex and hypoglossal motoneurons that can be taken up by 5-HT2A receptors in the absence of 5-HT2B receptors. The presence of functional 5-HT2B receptors in the neonatal medullary breathing center indicates a potential convergent regulatory role of 5-HT2B and -2A receptors on the central respiratory network (Gunther, 2006).
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