Nies Anne T, Spring Herbert, Thon Walter F, Keppler Dietrich, Jedlitschky Gabriele
Divisions of Tumor Biochemistry and Cell Biology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
J Urol. 2002 May;167(5):2271-5.
The intracellular messenger cyclic guanosine monophosphate (cGMP) has an important role in regulating smooth muscle tone. An increase in intracellular cGMP levels is a prerequisite for penile erection. Inhibition of cGMP degradation by cGMP specific phosphodiesterase 5 has been used for treating erectile dysfunction. In addition to degradation by phosphodiesterase, cGMP is exported from cells by multidrug resistance protein 5 (MRP5), also called ABCC5, which we recently identified as an adenosine triphosphate dependent export pump for cGMP. MRP5 is potently inhibited by substances known as phosphodiesterase inhibitors, including sildenafil and trequinsin. Therefore, we analyzed whether MRP5 is expressed in tissues of the human genitourinary system and whether MRP5 and phosphodiesterase 5 proteins are localized in the same cell types.
Localization of MRP5 and phosphodiesterase 5 was analyzed by immunofluorescence microscopy in cryosections of various tissues of the human genitourinary system.
MRP5 and phosphodiesterase 5 were co-expressed in smooth muscle cells of the corpus cavernosum, ureter, urethra and bladder. In addition, MRP5 and phosphodiesterase 5 were localized in epithelial cells of the mucosa in the ureter and urethra, and in blood vessels of the lamina propria.
The co-expression of MRP5 and phosphodiesterase 5 in smooth muscle cells of the genitourinary system indicates 2 distinct pathways for cGMP removal. Thus, MRP5 inhibition represents a new approach for enhancing cGMP levels in smooth muscle cells and developing drugs for erectile dysfunction.
细胞内信使环磷酸鸟苷（cGMP）在调节平滑肌张力中起重要作用。细胞内cGMP水平升高是阴茎勃起的前提条件。通过cGMP特异性磷酸二酯酶5抑制cGMP降解已被用于治疗勃起功能障碍。除了被磷酸二酯酶降解外，cGMP还通过多药耐药蛋白5（MRP5，也称为ABCC5）从细胞中输出，我们最近将其鉴定为一种依赖三磷酸腺苷的cGMP输出泵。MRP5受到包括西地那非和曲喹辛在内的磷酸二酯酶抑制剂的强烈抑制。因此，我们分析了MRP5是否在人类泌尿生殖系统组织中表达，以及MRP5和磷酸二酯酶5蛋白是否定位于相同的细胞类型。
通过免疫荧光显微镜分析MRP5和磷酸二酯酶5在人类泌尿生殖系统各种组织冰冻切片中的定位。
MRP5和磷酸二酯酶5在海绵体、输尿管、尿道和膀胱的平滑肌细胞中共表达。此外，MRP5和磷酸二酯酶5定位于输尿管和尿道黏膜的上皮细胞以及固有层的血管中。
MRP5和磷酸二酯酶5在泌尿生殖系统平滑肌细胞中的共表达表明存在两种不同的cGMP清除途径。因此，抑制MRP5代表了一种提高平滑肌细胞中cGMP水平以及开发治疗勃起功能障碍药物的新方法。
