Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 S Grand Boulevard, Saint Louis, Missouri 63104, USA.
J Endocrinol. 2013;218(2):B1-8.
Microvascular diseases, such as retinopathies, neuropathies, and nephropathies, are a devastating consequence of type 1 and type 2 diabetes. The etiology of diabetes-associated microvascular dysfunction is poorly understood, and, likewise, treatment modalities for these disorders are limited. Interestingly, proinsulin C-peptide has been shown to play a protective role against diabetes-associated complications in experimental animals and in diabetic humans and is thus an attractive therapeutic target. However, an important step in the development of C-peptide-based therapeutics is identification of the C-peptide receptor, which is likely a G protein-coupled receptor (GPCR). Using a unique Deductive Ligand-Receptor Matching Strategy, we sought to determine whether one of the known orphan GPCRs is essential for C-peptide signaling. Knockdown of GPR146, but not GPR107 or GPR160, blocked C-peptide-induced cFos expression in KATOIII cells. Furthermore, stimulation with C-peptide caused internalization of GPR146, and examples of punctate colocalization were observed between C-peptide and GPR146 on KATOIII cell membranes. These data indicate that GPR146 is likely a part of the C-peptide signaling complex and provide a platform for the elucidation of the C-peptide signalosome.
微血管疾病，如视网膜病变、神经病变和肾病，是 1 型和 2 型糖尿病的严重后果。糖尿病相关微血管功能障碍的病因尚不清楚，同样，这些疾病的治疗方法也有限。有趣的是，胰岛素原 C 肽已被证明在实验动物和糖尿病患者中对糖尿病相关并发症具有保护作用，因此是一种有吸引力的治疗靶点。然而，基于 C 肽的治疗方法的一个重要步骤是确定 C 肽受体，它可能是一种 G 蛋白偶联受体（GPCR）。我们使用独特的演绎配体-受体匹配策略，试图确定已知的孤儿 GPCR 之一是否对 C 肽信号传导至关重要。GPR146 的敲低，但不是 GPR107 或 GPR160，阻断了 KATOIII 细胞中 C 肽诱导的 cFos 表达。此外，C 肽刺激导致 GPR146 内化，并且在 KATOIII 细胞膜上观察到 C 肽和 GPR146 之间的点状共定位的例子。这些数据表明 GPR146 可能是 C 肽信号复合物的一部分，并为阐明 C 肽信号体提供了一个平台。
