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1.
Biol Pharm Bull ; 46(7): 869-873, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37394637

RESUMEN

Adrenergic receptors (ADRs) are widely distributed in the peripheral and central nervous systems. We previously reported that L-3,4-dihydroxyphenylalanine (L-DOPA), the precursor of dopamine, sensitizes adrenergic α1 receptor (ADRA1) through a G protein-coupled receptor GPR143. Chimeric analysis, in which the transmembrane (TM) domains of GPR143 were replaced with those of GPR37, revealed that the second TM region was essential for the potentiation of phenylephrine-induced extracellular signal-regulated kinase (ERK) phosphorylation by GPR143. In HEK293T cells expressing ADRA1B, phenylephrine-induced ERK phosphorylation was augmented by the co-expression of GPR143, compared to the mock vector. Immunoprecipitation analysis revealed that a synthetic transactivator of the transcription peptide fused with TM2 of GPR143 (TAT-TM2) disrupts the interaction between GPR143 and ADRA1B. This TAT-TM2 peptide suppressed the augmentation of phenylephrine-induced ERK phosphorylation by GPR143 in HEK293T cells co-expressing ADRA1B and GPR143. These results indicate that the interaction between GPR143 and ADRA1B is required for the potentiation of ADRA1B-mediated signaling by GPR143. The TM2 region of GPR143 is a crucial dimeric interface for the functional coupling between ADRA1B and GPR143.


Asunto(s)
Adrenérgicos , Dihidroxifenilalanina , Glicoproteínas de Membrana , Receptores Adrenérgicos alfa 1 , Humanos , Quinasas MAP Reguladas por Señal Extracelular , Proteínas del Ojo , Células HEK293 , Glicoproteínas de Membrana/metabolismo , Fenilefrina/farmacología , Receptores Adrenérgicos alfa 1/metabolismo
2.
J Immunol ; 201(2): 804-813, 2018 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-29898964

RESUMEN

In mice, fetal/neonatal B-1 cell development generates murine CD5+ B cells (B1a) with autoreactivity. We analyzed B1a cells at the neonatal stage in a VH11/D/JH knock-in mouse line (VH11t) that generates an autoreactive antiphosphatidylcholine BCR. Our study revealed that antiphosphatidylcholine B1a cells develop in liver, mature in spleen, and distribute in intestine/colon, mesenteric lymph node (mLN), and body cavity as the outcome of B-1 cell development before B-2 cell development. Throughout life, self-renewing B-1 B1a cells circulate through intestine, mesenteric vessel, and blood. The body cavity-deposited B1a cells also remigrate. In old age, some B1a cells proceed to monoclonal B cell lymphocytosis. When neonatal B-1 B1a cells express an antithymocyte/Thy-1 autoreactivity (ATA) BCR transgene in the C.B17 mouse background, ATA B cells increase in PBL and strongly develop lymphomas in aging mice that feature splenomegaly and mLN hyperplasia with heightened expression of CD11b, IL-10, and activated Stat3. At the adult stage, ATA B cells were normally present in the mantle zone area, including in intestine. Furthermore, frequent association with mLN hyperplasia suggests the influence by intestinal microenvironment on lymphoma development. When cyclin D1 was overexpressed by the Eµ-cyclin D1 transgene, ATA B cells progressed to further diffused lymphoma in aged mice, including in various lymph nodes with accumulation of IgMhiIgDloCD5+CD23-CD43+ cells, resembling aggressive human mantle cell lymphoma. Thus, our findings reveal that early generated B cells, as an outcome of B-1 cell development, can progress to become lymphocytosis, lymphoma, and mantle cell lymphoma-like neoplasia in aged mice.


Asunto(s)
Envejecimiento/inmunología , Linfocitos B/patología , Linfoma de Células del Manto/inmunología , Envejecimiento/patología , Animales , Autoantígenos/inmunología , Carcinogénesis , Diferenciación Celular , Ciclina D1/genética , Ciclina D1/metabolismo , Técnicas de Sustitución del Gen , Linfoma de Células del Manto/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosfatidilcolinas/inmunología , Receptores de Antígenos de Linfocitos B/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo
3.
JCI Insight ; 2(18)2017 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-28931752

RESUMEN

Blood pressure is regulated by extrinsic factors including noradrenaline, the sympathetic neurotransmitter that controls cardiovascular functions through adrenergic receptors. However, the fine-tuning system of noradrenaline signaling is relatively unknown. We here show that l-3,4-dihydroxyphenylalanine (L-DOPA), a precursor of catecholamines, sensitizes the vascular adrenergic receptor alpha1 (ADRA1) through activation of L-DOPA receptor GPR143. In WT mice, intravenous infusion of the ADRA1 agonist phenylephrine induced a transient elevation of blood pressure. This response was attenuated in Gpr143 gene-deficient (Gpr143-/y) mice. Specific knockout of Gpr143 in vascular smooth muscle cells (VSMCs) also showed a similar phenotype, indicating that L-DOPA directly modulates ADRA1 signaling in the VSMCs. L-DOPA at nanomolar concentrations alone produced no effect on the VSMCs, but it enhanced phenylephrine-induced vasoconstriction and intracellular Ca2+ responses. Phenylephrine also augmented the phosphorylation of extracellular signal-regulated kinases in cultured VSMCs from WT but not Gpr143-/y mice. In WT mice, blood pressure increased during the transition from light-rest to dark-active phases. This elevation was not observed in Gpr143-/y mice. Taken together, our findings provide evidence for L-DOPA/GPR143 signaling that exerts precursor control of sympathetic neurotransmission through sensitizing vascular ADRA1.


Asunto(s)
Levodopa/farmacología , Tono Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Animales , Calcio/metabolismo , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Noqueados , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiología , Fenilefrina/farmacología , Fosforilación , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Vasoconstrictores/farmacología
4.
Chem Commun (Camb) ; 47(31): 8835-7, 2011 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-21743892

RESUMEN

A LDL particle functionalized with a GdDO3A-monoamide chelate with a long alkenyl anchor (GdDO3A-OA) was prepared for in vivo detection of atheroplaques. The GdDO3A-OA, when successfully intercalated into the lipid layer of LDL particles, led to a significant enhancement of magnetic resonance imaging signal intensity of atheroplaques in atherosclerosis mouse models.


Asunto(s)
Medios de Contraste/química , Lipoproteínas LDL/química , Nanopartículas del Metal/química , Animales , Aterosclerosis/diagnóstico por imagen , Medios de Contraste/farmacocinética , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Modelos Animales de Enfermedad , Gadolinio/química , Compuestos Heterocíclicos con 1 Anillo/química , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Imagen por Resonancia Magnética , Ratones , Ratones Noqueados , Cintigrafía
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