Evidence for an interaction between proinsulin C-peptide and GPR146

被引:83
作者
Yosten, Gina L. C. [1 ]
Kolar, Grant R. [2 ]
Redlinger, Lauren J. [1 ]
Samson, Willis K. [1 ]
机构
[1] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA
[2] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA
关键词
C-peptide; GPR146; orphan GPCR; insulin receptor; PROTEIN-COUPLED RECEPTOR; NEURONOSTATIN; COMPLICATIONS; FAMILY;
D O I
10.1530/JOE-13-0203
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:B1 / B8
页数:8
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