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1.
Mol Pain ; 1: 3, 2005 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-15813989

RESUMEN

Prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) are major inflammatory mediators that play important roles in pain sensation and hyperalgesia. The role of their receptors (EP and IP, respectively) in inflammation has been well documented, although the EP receptor subtypes involved in this process and the underlying cellular mechanisms remain to be elucidated. The capsaicin receptor TRPV1 is a nonselective cation channel expressed in sensory neurons and activated by various noxious stimuli. TRPV1 has been reported to be critical for inflammatory pain mediated through PKA- and PKC-dependent pathways. PGE2 or PGI2increased or sensitized TRPV1 responses through EP1 or IP receptors, respectively predominantly in a PKC-dependent manner in both HEK293 cells expressing TRPV1 and mouse DRG neurons. In the presence of PGE2 or PGI2, the temperature threshold for TRPV1 activation was reduced below 35 degrees C, so that temperatures near body temperature are sufficient to activate TRPV1. A PKA-dependent pathway was also involved in the potentiation of TRPV1 through EP4 and IP receptors upon exposure to PGE2 and PGI2, respectively. Both PGE2-induced thermal hyperalgesia and inflammatory nociceptive responses were diminished in TRPV1-deficient mice and EP1-deficient mice. IP receptor involvement was also demonstrated using TRPV1-deficient mice and IP-deficient mice. Thus, the potentiation or sensitization of TRPV1 activity through EP1 or IP activation might be one important mechanism underlying the peripheral nociceptive actions of PGE2 or PGI2.


Asunto(s)
Nociceptores/metabolismo , Prostaglandinas/fisiología , Receptores de Prostaglandina E/fisiología , Receptores de Prostaglandina/fisiología , Canales Catiónicos TRPV/metabolismo , Animales , Línea Celular , Dinoprostona/administración & dosificación , Dinoprostona/metabolismo , Dinoprostona/fisiología , Sinergismo Farmacológico , Calor , Humanos , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Hiperalgesia/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Epoprostenol , Receptores de Prostaglandina/deficiencia , Receptores de Prostaglandina/genética , Receptores de Prostaglandina E/deficiencia , Receptores de Prostaglandina E/genética , Subtipo EP1 de Receptores de Prostaglandina E , Canales Catiónicos TRPV/deficiencia , Canales Catiónicos TRPV/genética
2.
Nat Immunol ; 6(5): 524-31, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15806106

RESUMEN

Prostaglandins, including PGD(2) and PGE(2), are produced during allergic reactions. Although PGD(2) is an important mediator of allergic responses, aspirin-like drugs that inhibit prostaglandin synthesis are generally ineffective in allergic disorders, suggesting that another prostaglandin-mediated pathway prevents the development of allergic reactions. Here we show that such a pathway may be mediated by PGE(2) acting at the prostaglandin E receptor EP3. Mice lacking EP3 developed allergic inflammation that was much more pronounced than that in wild-type mice or mice deficient in other prostaglandin E receptor subtypes. Conversely, an EP3-selective agonist suppressed the inflammation. This suppression was effective when the agonist was administered 3 h after antigen challenge and was associated with inhibition of allergy-related gene expression. Thus, the PGE(2)-EP3 pathway is an important negative modulator of allergic reactions.


Asunto(s)
Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Receptores de Prostaglandina E/metabolismo , Alérgenos/inmunología , Alérgenos/farmacología , Animales , Dinoprostona/agonistas , Eliminación de Gen , Regulación de la Expresión Génica , Hipersensibilidad/genética , Hipersensibilidad/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Noqueados , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E/deficiencia , Receptores de Prostaglandina E/genética , Subtipo EP3 de Receptores de Prostaglandina E
3.
J Biol Chem ; 278(20): 18597-605, 2003 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-12637513

RESUMEN

During a screen for novel putative Ca(2+)/calmodulin-dependent protein kinase (CaMK)-like CREB kinases (CLICKs), we have cloned a full-length cDNA for CLICK-III/CaMKIgamma, an isoform of the CaMKI family with an extended C-terminal domain ending with CAAX motif (where AA is aliphatic acid). As expected from the similarity of its kinase domain with the other CaMKI isoforms, full activation of CLICK-III/CaMKIgamma required both Ca(2+)/CaM and phosphorylation by CaMKK. We also found that Ca(2+)/cAMP-response element-binding protein (CREB) was a good substrate for CLICK-III/CaMKIgamma, at least in vitro. Interestingly enough, CLICK-III/CaMKIgamma transcripts were most abundant in neurons, with the highest levels in limited nuclei such as the central nucleus of the amygdala (CeA) and the ventromedial hypothalamus. Consistent with the presence of the CAAX motif, CLICK-III/CaMKIgamma was found to be anchored to various membrane compartments, especially to Golgi and plasma membranes. Both point mutation in the CAAX motif and treatment with compactin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, disrupted such membrane localization, suggesting that membrane localization of CLICK-III/CaMKIgamma occurred in a prenylation-dependent way. These findings provide a novel mechanism by which neuronal CaMK activity could be targeted to specific membrane compartments.


Asunto(s)
Proteínas Quinasas Dependientes de Calcio-Calmodulina/química , Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Membrana Celular/enzimología , Lovastatina/análogos & derivados , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Northern Blotting , Western Blotting , Células COS , Calcio/metabolismo , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Células Cultivadas , Clonación Molecular , Aparato de Golgi/enzimología , Humanos , Hipotálamo/metabolismo , Hibridación in Situ , Lovastatina/farmacología , Luciferasas/metabolismo , Proteínas de la Membrana , Ratones , Ratones Endogámicos ICR , Microscopía Fluorescente , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Plásmidos/metabolismo , Pruebas de Precipitina , Estructura Terciaria de Proteína , Homología de Secuencia de Aminoácido , Fracciones Subcelulares/metabolismo , Distribución Tisular , Transfección
4.
Biol Reprod ; 68(3): 804-11, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12604629

RESUMEN

Prostaglandin (PG) E(2) is synthesized from arachidonic acid by cyclooxygenase (COX) and acts as a regulator in ovulation and fertilization reactions. We present the temporal and regional expression patterns of mRNAs for the two Gs-coupled PGE receptors, EP2 and EP4, and for COX-1 and COX-2 in mouse periovulatory follicles and oviducts during superovulation. Analysis using reverse transcription polymerase chain reaction revealed that the mouse ovaries express a significant amount of EP4 mRNA in addition to EP2 mRNA during superovulation. In situ hybridization results revealed that the signals for EP4 mRNA were localized mostly to oocytes in the preantral follicles. Three hours after hCG injection, the signals for EP4 and EP2 mRNA were present in both granulosa and cumulus cells. However, 9 h after hCG injection, just before ovulation, the signals for EP4 mRNA were still detectable in both cell types, whereas those for EP2 mRNA were found only in cumulus cells. COX-2 mRNA expression was present in both granulosa and cumulus cells at 3 h but was present only in cumulus cells at 9 h. COX-1 mRNA expression was not found in granulosa cells at 3 h but was found in these cells at 9 h. In the oviduct, the expression of EP4 and COX-1 mRNA was localized to epithelial cells, whereas expression of EP2 mRNA was localized to the smooth muscle layer. The tightly regulated expression of both EP2 and EP4 in the preovulatory follicles may reflect the essential role of PGE(2) in the ovulation process.


Asunto(s)
Trompas Uterinas/metabolismo , Isoenzimas/biosíntesis , Folículo Ovárico/metabolismo , Prostaglandina-Endoperóxido Sintasas/biosíntesis , ARN Mensajero/biosíntesis , Receptores de Prostaglandina E/biosíntesis , Animales , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Trompas Uterinas/enzimología , Femenino , Regulación Enzimológica de la Expresión Génica , Hibridación in Situ , Isoenzimas/genética , Proteínas de la Membrana , Ratones , Ratones Endogámicos C57BL , Folículo Ovárico/enzimología , Ovulación/fisiología , Prostaglandina-Endoperóxido Sintasas/genética , ARN Mensajero/genética , Receptores de Prostaglandina E/genética , Subtipo EP2 de Receptores de Prostaglandina E , Subtipo EP4 de Receptores de Prostaglandina E , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
5.
J Clin Invest ; 109(7): 883-93, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11927615

RESUMEN

We used mice deficient in each of the eight types and subtypes of prostanoid receptors and examined the roles of prostanoids in dextran sodium sulfate-induced (DSS-induced) colitis. Among the prostanoid receptor-deficient mice, only EP4-deficient mice and not mice deficient in either DP, EP1, EP2, EP3, FP, IP, or TP developed severe colitis with 3% DSS treatment, which induced only marginal colitis in wild-type mice. This phenotype was mimicked in wild-type mice by administration of an EP4-selective antagonist (AE3-208). The EP4 deficiency impaired mucosal barrier function and induced epithelial loss, crypt damage, and aggregation of neutrophils and lymphocytes in the colon. Conversely, administration of an EP4-selective agonist (AE1-734) to wild-type mice ameliorated severe colitis normally induced with 7% DSS, while that of AE3-208 suppressed recovery from colitis and induced significant proliferation of CD4+ T cells. In vitro AE3-208 enhanced and AE1-734 suppressed the proliferation and Th1 cytokine production of lamina propria mononuclear cells from the colon. DNA microarray analysis revealed elevated expression of genes associated with immune response and reduced expression of genes with mucosal repair and remodeling in the colon of EP4-deficient mice. We conclude that EP4 maintains intestinal homeostasis by keeping mucosal integrity and downregulating immune response.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Colon/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Activación de Linfocitos/inmunología , Receptores de Prostaglandina E/inmunología , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Linfocitos T CD4-Positivos/efectos de los fármacos , División Celular , Colon/efectos de los fármacos , Colon/patología , Sulfato de Dextran/efectos adversos , Dinoprostona/inmunología , Dinoprostona/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Indometacina/efectos adversos , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/fisiopatología , Interferón gamma/biosíntesis , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E/antagonistas & inhibidores , Receptores de Prostaglandina E/genética , Subtipo EP4 de Receptores de Prostaglandina E , Transducción de Señal/inmunología , Células TH1/inmunología
6.
Proc Natl Acad Sci U S A ; 99(7): 4580-5, 2002 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-11917107

RESUMEN

Bone remodeling, comprising resorption of existing bone and de novo bone formation, is required for the maintenance of a constant bone mass. Prostaglandin (PG)E2 promotes both bone resorption and bone formation. By infusing PGE2 to mice lacking each of four PGE receptor (EP) subtypes, we have identified EP4 as the receptor that mediates bone formation in response to this agent. Consistently, bone formation was induced in wild-type mice by infusion of an EP4-selective agonist and not agonists specific for other EP subtypes. In culture of bone marrow cells from wild-type mice, PGE2 induced expression of core-binding factor alpha1 (Runx2/Cbfa1) and enhanced formation of mineralized nodules, both of which were absent in the culture of cells from EP4-deficient mice. Furthermore, administration of the EP4 agonist restored bone mass and strength normally lost in rats subjected to ovariectomy or immobilization. Histomorphometric analysis revealed that the EP4 agonist induced significant increases in the volume of cancellous bone, osteoid formation, and the number of osteoblasts in the affected bone of immobilized rats, indicating that activation of EP4 induces de novo bone formation. In addition, osteoclasts were found on the increased bone surface at a density comparable to that found in the bone of control animals. These results suggest that activation of EP4 induces bone remodeling in vivo and that EP4-selective drugs may be beneficial in humans with osteoporosis.


Asunto(s)
Resorción Ósea/prevención & control , Dinoprostona/farmacología , Osteogénesis/efectos de los fármacos , Receptores de Prostaglandina E/agonistas , Animales , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Osteoblastos/efectos de los fármacos , Osteoporosis/prevención & control , Ovariectomía , Ratas , Ratas Sprague-Dawley , Receptores de Prostaglandina E/fisiología , Subtipo EP4 de Receptores de Prostaglandina E
7.
J Hepatol ; 36(3): 328-34, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11867175

RESUMEN

BACKGROUND/AIMS: Prostaglandin E2 (PGE2) is known to inhibit the lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) formation in Kupffer cells via an increase in cAMP. Four receptor-subtypes have been cloned for PGE2 so far. Two of them, the EP2-receptor and the EP4-receptor are linked to stimulatory Gs-proteins and could mediate the inhibition by PGE2 of TNFalpha-formation. METHODS: The significance of both receptors for PGE2-dependent inhibition of LPS-induced TNFalpha-formation was studied using Kupffer cells of mice in which either one of the two receptors had been eliminated by homologous recombination. RESULTS: The mRNAs of both receptors were expressed in wild type mouse Kupffer cells. Exogenous PGE2 inhibited TNFalpha-formation in Kupffer cells lacking either EP2-receptor or EP4-receptor to a similar extent as in control cells, however, 10-fold higher PGE2 concentrations were needed for half maximal inhibition in cells lacking the EP4-receptor than in control or EP2-receptor-deficient cells. The response to endogenous PGE2 was blunted in EP4-receptor-deficient mice only and especially after prolonged incubation. CONCLUSIONS: The data indicate, that PGE2 can inhibit TNFalpha-formation via both the EP2- and the EP4-receptor and that, however, the EP4-receptor appears to be physiologically more relevant in Kupffer cells since it conferred a high affinity response to PGE2.


Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Macrófagos del Hígado/metabolismo , Receptores de Prostaglandina E/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Células Cultivadas , AMP Cíclico/metabolismo , Dinoprostona/farmacología , Relación Dosis-Respuesta a Droga , Expresión Génica/inmunología , Hepatitis/inmunología , Hepatitis/metabolismo , Macrófagos del Hígado/citología , Macrófagos del Hígado/inmunología , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E/genética , Subtipo EP2 de Receptores de Prostaglandina E , Subtipo EP4 de Receptores de Prostaglandina E
8.
Biochem Biophys Res Commun ; 290(2): 696-700, 2002 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-11785955

RESUMEN

We investigated the mRNA distribution of the prostaglandin (PG) E(2) receptor subtypes and cyclooxygenases (COXs) in hair follicles of the mouse dorsal skin. In the 3-week hair follicles, which are in the anagen phase, EP3 and EP4 mRNA were expressed in the dermal papilla cells and the outer root sheath cells located in the hair bulb region, respectively. In the 8-week hair follicles, which are in the telogen phase, the signals for both EP3 and EP4 mRNAs had disappeared. To study the hair cycle-dependent expression of mRNAs for the EPs and COXs, an area of dorsal hair was depilated from 8-week-old mice. On days 8 and 12 after depilation, EP3 and EP4 mRNA were reexpressed in the dermal papilla cells and the outer root sheath cells, and the induction of COX-2 mRNA was also observed in the outer root sheath cells, the upper area of EP4 expression site. These results suggest that EP3 and EP4 receptors may involve in the development and regrowth of the hair follicles.


Asunto(s)
Folículo Piloso/metabolismo , ARN Mensajero/biosíntesis , Receptores de Prostaglandina E/biosíntesis , Animales , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inducción Enzimática/fisiología , Folículo Piloso/citología , Hibridación in Situ , Isoenzimas/biosíntesis , Isoenzimas/genética , Masculino , Proteínas de la Membrana , Ratones , Ratones Endogámicos C57BL , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Prostaglandina-Endoperóxido Sintasas/genética , Receptores de Prostaglandina E/genética
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