RESUMEN
We report the discovery and initial characterization of a novel class of selective NPFF2 agonists. HTS screening using R-SAT, a whole cell based functional assay, identified a class of aryliminoguanidines as NPFF1 and NPFF2 ligands. Subsequent optimization led to molecules exhibiting selective NPFF2 agonistic activity. Systemic administration showed that selective NPFF2 agonists (1 and 3) are active in various pain models in vivo, whereas administration of a nonselective NPFF1 and NPFF2 agonist (9) increases sensitivity to noxious and non-noxious stimuli.
Asunto(s)
Analgésicos/síntesis química , Guanidinas/síntesis química , Receptores de Neuropéptido/agonistas , Analgésicos/química , Analgésicos/farmacología , Animales , Carragenina , Guanidinas/química , Guanidinas/farmacología , Humanos , Técnicas In Vitro , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Microsomas Hepáticos/metabolismo , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Dimensión del Dolor , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Ratas , Receptores de Neuropéptido/antagonistas & inhibidoresRESUMEN
The expression and organization of the phototransduction signaling proteins into a specialized light-sensing organelle, the rhabdomere, is required for photoreceptor cells to detect light. We report the characterization of the mutant Pph13(hazy). Pph13 is a homeodomain transcription factor expressed only in photoreceptor cells. Pph13 expression correlates with the differentiation and not specification of photoreceptor cells. In agreement with its expression profile, we find Pph13 is required for both rhabdomere morphogenesis and for the proper detection of light. In addition, we demonstrate that Pph13 exerts its effect by the regulation of photoreceptor specific gene expression.
Asunto(s)
Drosophila melanogaster/embriología , Drosophila/metabolismo , Proteínas del Ojo/metabolismo , Proteínas de Homeodominio/metabolismo , Morfogénesis , Visión Ocular/fisiología , Animales , Diferenciación Celular/fisiología , Linaje de la Célula , Drosophila/genética , Proteínas de Drosophila , Drosophila melanogaster/anatomía & histología , Drosophila melanogaster/genética , Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Luz , Mutación , Células Fotorreceptoras de Invertebrados/anatomía & histología , Células Fotorreceptoras de Invertebrados/patología , Células Fotorreceptoras de Invertebrados/fisiología , Transcripción GenéticaRESUMEN
Elucidating the mechanisms that link the circadian pacemaker to the timing of behaviors it controls is one of the greatest challenges in circadian biology. We report the generation of a P element, Pluc+, containing a novel reporter fusion. Our fusion reporter capitalizes on the use of luciferase bioluminescence to easily analyze temporal expression as well as the strength of myc epitopes and GFP to identify spatial expression. Using Pluc+ we have identified and characterized a novel C2H2 zinc-finger gene, regular (rgr), that cycles circadianly in phase with period (per) gene expression, but shifts to light-dark regulation in Clk(Jrk) mutant flies. By following myc expression of the Pluc+ reporter, we demonstrate that Rgr is expressed in a discrete number of neurons in the brain which overlap with axons expressing pigment-dispersing factor.