Endocrine Abstracts (2011) 26 OC5.4

Adrenal melanocortin 2 receptor associated protein (MRAP) expression is regulated by ACTH and angiotensin II, whereas MRAP2 levels are associated with ACTH responsiveness

J Hofland, P J Delhanty, J Steenbergen, L J Hofland, P M van Koetsveld, F H van Nederveen, W W de Herder, R A Feelders & F H de Jong

Erasmus MC, Rotterdam, The Netherlands.

Introduction: ACTH stimulates adrenocortical steroid production through the melanocortin 2 receptor (MC2R). MC2R trafficking and signaling depend on the melanocortin 2 receptor accessory protein (MRAP). The MRAP-homolog MRAP2 also transports the MC2R but prevents effective activation. We investigated expression of these components of the MC2R complex in human adrenal tissues in order to uncover novel regulatory mechanisms and their contribution to ACTH responsiveness.

Methods: Expression levels of MRAP, MRAP2 and MC2R were studied in adrenal tissues from 37 patients and related to clinical data. Primary adrenal cultures from 40 patients were stimulated with ACTH, forskolin, angiotensin (Ang)II or PMA in order to study the regulation of expression of these mRNAs. Induction of ACTH-responsive genes was related to MRAP, MRAP2 and MC2R mRNA expression levels.

Results: MRAP and MRAP2 levels were lower in adrenocortical carcinomas (ACCs) than in adrenal ACTH-dependent or -independent hyperplasia or adenoma tissues (P<0.001), whereas MC2R levels were comparable in all groups. The expression of MRAP, MRAP2 and MC2R did not differ between ACTH-dependent or -independent hyperplasia. Patient plasma ACTH and serum cortisol levels were positively associated with MRAP and MC2R levels in adrenal hyperplasia samples (P<0.05), but not in tumors. In vitro, ACTH and forskolin both potently induced expression of MRAP and MC2R in all adrenal tissue types (P<0.0001), whereas AngII augmented these mRNAs in all tissue types as well (P<0.001), with the exception of ACCs. MRAP2 expression was reduced by PMA (P=0.001). The ACTH induction of CYP21A2 relative to that by forskolin was inversely related to MRAP2 levels (r=−0.84, P=0.038), whereas there was no association between MRAP or MC2R expression and ACTH responsiveness.

Conclusions: MRAP and MC2R are controlled by ACTH and AngII, but expression levels do not directly relate to ACTH responsiveness. MRAP2 levels are negatively associated with the effects of ACTH.