RESUMEN
The 386 human SLC superfamily members are diverse in sequence, structure, and function. Using sequence similarity, we previously classified the SLC superfamily members and identified relationships among families. With the recent determination of new SLC structures and identification of previously unknown human SLC families, an update of our previous classification is timely. Here, we comprehensively compare the SLC sequences and structures and discuss the applicability of structure-based ligand discovery to key SLC members.
Asunto(s)
Proteínas de Transporte de Membrana/clasificación , Secuencia de Aminoácidos , Transporte Biológico , Evolución Molecular , Humanos , Ligandos , Proteínas de Transporte de Membrana/química , Modelos Teóricos , Alineación de SecuenciaRESUMEN
Multidrug and toxin extrusion 2 (MATE2-K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized genetic variants of MATE2-K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2-K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants-c.485C>T and c.1177G>A-were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2-K basal promoter haplotypes containing the most common variant, g.-130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF-1). Patients with diabetes who were homozygous for g.-130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (-0.027 (-0.076, 0.033)), as compared with carriers of the reference allele, g.-130G (-0.15 (-0.17, -0.13)) (P=0.002). Our study showed that MATE2-K plays a role in the antidiabetes response to metformin.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacocinética , Metformina/farmacocinética , Proteínas de Transporte de Catión Orgánico/genética , Adulto , Anciano , Alelos , Animales , Femenino , Variación Genética , Hemoglobina Glucada/metabolismo , Células HCT116 , Células HEK293 , Haplotipos , Humanos , Hipoglucemiantes/farmacología , Células LLC-PK1 , Luciferasas/metabolismo , Masculino , Metformina/farmacología , Persona de Mediana Edad , Polimorfismo Genético , Regiones Promotoras Genéticas , Grupos Raciales/genética , Estudios Retrospectivos , Porcinos , Resultado del TratamientoRESUMEN
The dentate gyrus of the rat contains about 600,000 granule cells. These small neurons are generated over a prolonged period from the 14th day of gestation until some time after the second postnatal week. The majority of the cells pass through their last phase of DNA synthesis in the postnatal period, and during the peak period of cell generation, between the fifth and seventh days after birth, up to 50,000 granule cells are formed each day. Contrary to earlier reports, most of the cells pass through their last mitotic division either within the stratum granulosum itself, or within the hilar region of the developing gyrus. The precursor population of cells in the hilar region must therefore constitute a pool of true neuroblasts. The origin of this pool of cells has not been definitely established but it seems probable that its cells are derived from the neuroepithelium lining the lateral ventricle adjacent to the region from which the hippocampal pyramidal cells are generated. Examination of the final location of granule cells labeled at different stages reveals three distinct morphogenetic gradients in the gyrus. The cells in the dorsal blade tend to be formed earlier than those in the ventral blade; cells in the more caudal (or temporal) portions of the gyrus are generated earlier than those in more rostral (or septal) regions; and in all regions the more superficial neurons in the stratum granulosum are formed earlier than the deeper granule cells. The bearing of some of these findings on the development and organization of the connections of the dentate gyrus is discussed.