Molecular determinants of melatonin signaling dysfunction in adolescent idiopathic scoliosis.
Presently, the genetic cause of adolescent idiopathic scoliosis (AIS), the most common form of scoliosis, remains unclear. Among many hypotheses, the neuroendocrine hypothesis involving a melatonin deficiency as the source for AIS generated the greatest interest and controversy since no decrease in circulating melatonin level has been observed in a majority of studies. Previously, we have reconciled the role of melatonin in AIS by demonstrating a melatonin signaling dysfunction occurring in osteoblasts derived from AIS patients, which contrasted with similar cells isolated from healthy subjects. We found that this difference is caused in AIS cells by increased phosphorylation of serine residues affecting the activity of G inhibitory proteins normally associated with melatonin cell surface receptors. Here we propose a preliminary molecular classification of patients with AIS based on the cellular response to the melatonin (cAMP) and distinct protein-protein interactions. These interactions include those between protein kinase C delta (PKCdelta) and MT2 melatonin receptors or PKCdelta and the receptor for activated protein C kinase 1. This finding could help in future molecular classification of patients with AIS.
Azeddine
Bouziane
B
Research Centre, Sainte-Justine University Hospital, Montreal, Canada.
Letellier
Kareen
K
Wang
Da Shen
da S
Moldovan
Florina
F
Moreau
Alain
A
D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008550:Melatonin / Q000378:metabolism* / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism; D012600:Scoliosis / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
D004338:Drug Combinations; D044123:Receptor, Melatonin, MT2; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D005576:Colforsin; D000242:Cyclic AMP; D051745:Protein Kinase C-delta; D000262:Adenylyl Cyclases; D008550:Melatonin