NEFM (Neurofilament Medium) Polypeptide, a Marker for Zona Glomerulosa Cells in Human Adrenal, Inhibits D1R (Dopamine D1 Receptor)–Mediated Secretion of Aldosterone

Abstract

A ldosterone-producing adenomas (APAs) are responsible for ≈5% of hypertension and are probably its most common curable cause. 1 The heterogeneity of these tumors has been highlighted by the landmark discovery of somatic mutations of KCNJ5, followed by others in ATP2B3, ATP1A1, CACNA1D, and CTNNB1. [2][3][4][5] The genotype and histological features delineate 2 overlapping APA subtypes: the common, large KCNJ5 mutant APAs histology is usually similar to cortisol-producing zona fasciculata (ZF) and smaller APAs with other mutations are mainly composed of zona glomerulosa (ZG)-like compact, lipid-depleted cells.The 2 subtypes present other phenotypic differences: for instance, elevated secretion from an APA of hybrid steroids 18-hydroxycortisol and 18-oxocortisol could be considered a fingerprint of KCNJ5 mutation.6 Further differences about the response to aldosterone secretagogues, such as angiotensin II or metoclopramide, have been previously reported. 7,8 Dopamine is one of the main regulators of aldosterone secretion. 9 The 5 known dopamine receptors belong to the G-protein-coupled receptor superfamily and are classified into 2 major subgroups (D1-like and D2-like) according to their structure and opposite action on cAMP production. Activation of the D1-like subfamily members (D1R and D5R) causes an increase of intracellular cAMP levels. The D2-like subfamily includes D2R, D3R, and D4R receptors; their transduction of signal causes a reduction of cAMP production. 10In human adrenal, most attention has been paid to the D2R subtype. This is expressed in normal ZG and mediates dopamine inhibition of aldosterone response to angiotensin II (but not to adrenocorticotropic hormone or potassium) 11,12 and tonic

The Many Faces of Primary Aldosteronism and Cushing Syndrome: A Reflection of Adrenocortical Tumor Heterogeneity

“…Understanding the functional and cellular correlates of the previously discussed ion channel-related molecular alterations has transformed the field of primary aldosteronism by expanding the role of biomarkers including but not limited to CYP11B2, CD56, and Dab2 (Table 1 ) ( 26 – 28 ). Several lines of evidence suggest that there is strong genotype ( KCNJ5, ATP1A1, ATP2B3 , and CACNA1D ) and phenotype correlation with respect to patient demographics ( 16 , 22 , 29 ), degree of aldosteronism ( 29 ), tumor size ( 16 – 18 , 22 , 29 ) and focality ( 11 , 22 ), tumor cytomorphology ( 11 , 14 – 18 , 29 ), proliferative capacity ( 15 ), and expression for CYP11B1, CYP17, and CYP11B2 in aldosterone-producing adenomas ( 14 – 18 ), as well as in APCCs (as discussed above).…”

“…The significant differences between KCNJ5 mutant and wild-type tumors initiated a scientific discussion on the possibility that tumor formation and hyperfunctionality may represent independent processes ( 14 ). While these findings question the ZG origin of KCNJ5- mutant adenomas, it also raises the possibility that KCNJ5- mutant tumors may arise from existing adrenal cortical nodules that undergo functional dysregulation, a hypothesis that requires further investigation ( 27 , 28 ). A recent series reported significantly higher Ki-67 proliferation indices (although all groups had Ki-67 labeling indices <5%) in CACNA1D- and ATP1A1- mutant tumors than in those harboring KCNJ5 mutations ( 15 ).…”

Review of Markers of Zona Glomerulosa and Aldosterone-Producing Adenoma Cells

“…56 Silencing of NEFM in H295R cells increased aldosterone production and decreased CYP11B2 and NR4A2 mRNA expression levels, and also enhanced cell proliferation, suggesting that NEFM suppresses aldosterone synthesis and growth. 56 NEFM interacts with dopamine receptor D1, which stimulates aldosterone secretion in both ZG and ZG-like APAs cells. 56 NEFM, by binding D1 receptor and internalizing it, promotes its desensitization and therefore blunts aldosterone secretion.…”

“…56 NEFM interacts with dopamine receptor D1, which stimulates aldosterone secretion in both ZG and ZG-like APAs cells. 56 NEFM, by binding D1 receptor and internalizing it, promotes its desensitization and therefore blunts aldosterone secretion. 56 Because of the specific expression in ZG-like APAs, NEFM could be useful for identification of ZG-like APAs.…”

“…56 NEFM, by binding D1 receptor and internalizing it, promotes its desensitization and therefore blunts aldosterone secretion. 56 Because of the specific expression in ZG-like APAs, NEFM could be useful for identification of ZG-like APAs.…”