title: Evidence for an interaction between proinsulin C-peptide and GPR146.
abstract: 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.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 S Grand Boulevard, Saint Louis, Missouri 63104, USA. gyosten@slu.edu
authors.forename: Gina L C
authors.initials: GL
authors.lastname: Yosten
authors.forename: Grant R
authors.initials: GR
authors.lastname: Kolar
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Redlinger
authors.forename: Willis K
authors.initials: WK
authors.lastname: Samson
mesh_terms: D002096:C-Peptide / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D002096:C-Peptide; C583411:GPR146 protein, human; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; D011972:Receptor, Insulin
keywords: C-peptide; GPR146; insulin receptor; orphan GPCR