Nuclear Receptors As Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription
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cells Review Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription Dongyun Zhang 1 and Anthony P. Heaney 1,2,* 1 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; [email protected] 2 Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA * Correspondence: [email protected]; Tel.: +1-310-267-4980; Fax: +1-310-267-1899 Received: 22 February 2020; Accepted: 1 April 2020; Published: 7 April 2020 Abstract: The hypothalamic–pituitary–adrenal (HPA) axis plays a critical role in adaptive stress responses and maintaining organism homeostasis. The pituitary corticotroph is the central player in the HPA axis and is regulated by a plethora of hormonal and stress related factors that synergistically interact to activate and temper pro-opiomelanocortin (POMC) transcription, to either increase or decrease adrenocorticotropic hormone (ACTH) production and secretion as needed. Nuclear receptors are a family of highly conserved transcription factors that can also be induced by various physiologic signals, and they mediate their responses via multiple targets to regulate metabolism and homeostasis. In this review, we summarize the modulatory roles of nuclear receptors on pituitary corticotroph cell POMC transcription, describe the unique and complex role these factors play in hypothalamic–pituitary–adrenal axis (HPA) regulation and discuss potential therapeutic targets in disease states. Keywords: adrenocorticotropic hormone; corticotroph; glucocorticoids; hypothalamic–pituitary–adrenal axis; nuclear receptor; pro-opiomelanocortin 1. Introduction The pituitary gland serves as a critical anatomical and functional connection between central and multiple peripheral endocrine organs (Figure1A). It comprises two embryonically distinct components, namely the anterior pituitary (AP) that originates from the non-neural oral ectoderm and makes up ~2/3 of the gland, and the posterior pituitary (PP) which develops from the anterior neural plate [1]. Communicating between the hypothalamus, and the adrenal, thyroid, liver, gonads and the anterior pituitary interprets fluctuating levels of neuropeptides and steroid hormones from the hypophyseal portal veins and the circulating bloodstream to coordinate production and release of six bioactive pituitary-derived peptide hormones, namely adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and prolactin (PRL). In contrast, the posterior pituitary is a direct extension of the hypothalamic magnocellular neurons (MN) of the paraventricular and supraoptic nuclei (PVN and SON) which travel downward along the pituitary stalk (Figure1B). It stores and releases arginine vasopressin hormone (AVP) and oxytocin (OXT) which maintain water balance and regulate parturition and breast milk release respectively. Arguably, the most critical component of this three-tier system is the hypothalamic–pituitary– adrenal (HPA) axis which plays a vital role in adaptive stress responses and maintaining organism homeostasis. The hypothalamic neurons in the medial parvocellular (MP) subdivision of the PVN synthesize and secrete corticotropin-releasing hormone (CRH), which travels through the hypophyseal Cells 2020, 9, 900; doi:10.3390/cells9040900 www.mdpi.com/journal/cells Cells 20202020, 9, 900x FOR PEER REVIEW 2 of 33 32 hypophyseal portal vessels to reach the anterior pituitary gland (Figure 1B). CRH then binds to portalcorticotropin vessels toreleasing reach the hormone anterior pituitaryreceptor- gland1 (CRH (Figure-R1) 1whichB). CRH is thenspecifically binds to expresse corticotropind on releasing anterior pituitaryhormone receptor-1corticotroph (CRH-R1) cells to which stimulate is specifically the release expressed of ACTH on anterior into the pituitary systemic corticotroph circulation. cells The to principalstimulate thetarget release for circulating of ACTH into ACTH the systemicis the adrenal circulation. cortex, The where principal on bind targetingfor its circulatingcognate receptor ACTH melanocortinis the adrenal cortex,2 receptor where (MC2R) on binding, ACTH its cognate primarily receptor induces melanocortin glucocorticoid 2 receptor (GC) (MC2R),synthesis ACTH and primarilysecretion from induces the glucocorticoidzona fasciculata (GC) of the synthesis adrenal and gland secretion [2]. GCs from are the pleiotropic zona fasciculata hormones, of the involved adrenal ingland almost [2]. GCsevery are cellular, pleiotropic molecular hormones, and involvedphysiologic in almost aspect every of the cellular, organism molecular and regulate and physiologic a broad spectrumaspect of theof essential organism physiologic and regulate functions. a broad spectrumGCs also of fine essential-tune HPA physiologic axis activity functions. by inhibiti GCs alsong hypothalamicfine-tune HPA CRH axis activity and anterior by inhibiting pituitary hypothalamic ACTH production CRH and and anterior secretion pituitary in a negative ACTH production feedback loopand secretionmanner ( inFigure a negative 1C). feedback loop manner (Figure1C). Hypothalamus B PVN SON 3V MPMP MN A MN VP PP AVP/OXT neuron CRH neuron AVP neuron Hypophyseal Portal Vessel ME CRH AP CRH-R1 Corticotroph Pituitary PP ACTH C Liver CRH/AVP release (+) (-) ACTH release (-) (+) Cortisol release Figure 1. SchematicSchematic diagram diagram of of the the hypothalamic hypothalamic-pituitary-adrenal-pituitary-adrenal (HPA) axis.axis. ( A) The major glands of the endocrine system include the hypothalamus and pituitary gland centrally and the thyroid, islet cells of of the the pancreas, pancreas, adrenal adrenal glands, glands, liver liver and and gonads gonads peripherally. peripherally. (B) ( BThe) The HPA HPA axis axis is regulated is regulated by hypothalamicby hypothalamic corticotropin corticotropin-releasing-releasing hormone hormone (CRH) (CRH) and and arginine arginine vasopressin vasopressin (AVP), (AVP), which which are produced in the paraventricular nucleus (PVN) of the hypothalamus and transported to the anterior pituitary, wherewhere they they drive drive synthesize synthesize and and secretion secretion of pituitary of pituitary adrenocorticotropic adrenocorticotropic hormone hormone (ACTH). (ACTH).In the adrenal In the cortex, adrenal ACTH cortex, stimulates ACTH the stimulates adrenal zonathe adrenal fasciculata zona cortex fasciculata to release cortex glucocorticoids to release (GCs),glucocorticoids which have (GCs), numerous which physiological have numerous effects. physiological (C) GCs also effects. exert negative (C) GCs feedback also exert at the negative level of feedbackthe hypothalamus at the level and of pituitary the hypothalamus to dampen excessiveand pituitary activation to dampen of the excessive HPA axis. activation 3V, the third of the ventricle; HPA AP,axis. anterior 3V, the pituitary;third ventricle; ME, median AP, anterior eminence; pituitary; MP, medialME, median parvocellular; eminence; MN, MP, magnocellular medial parvocellular; nucleus; MN,OXT, oxytocin;magnocellular PP, periventricular nucleus; OXT, parvocellular; oxytocin; PP, SON, periventricular supraoptic nucleus; parvocellular; VP, ventral SON, parvocellular. supraoptic nucleus; VP, ventral parvocellular. Cells 2020, 9, x; doi: FOR PEER REVIEW www.mdpi.com/journal/cells Cells 20202020,, 9,, 900x FOR PEER REVIEW 3 of 33 32 2. Pituitary Specific Regulators of Pro-Opiomelanocortin Transcription 2. Pituitary Specific Regulators of Pro-Opiomelanocortin Transcription Pro-opiomelanocortin (POMC) belongs to an ancestral opioid/orphanin gene family, and arose over Pro-opiomelanocortin500 million years ago by (POMC) insertion belongs of the to melanocortin an ancestral opioidsequence/orphanin into a preproendorphin gene family, and arosegene [over3–5] 500. The million human years POMC ago bygene insertion is located of the on melanocortin chromosome sequence 2p23.3, intospanning a preproendorphin 7,999bp on the gene reverse [3–5]. Thestrand. human It contains POMC three gene isexons located (354 onbp chromosome, 152bp, and 2p23.3,900bp spanningrespectively) 7999 separated bp on the by reverse two introns strand. (3It, contains705bp and three 2,888 exonsbp respectively (354 bp, 152, bp,Figure and 2A 900). bpThe respectively) 5′-untranslated separated region by (5′ two-UTR) introns of POMC (3705 mRNA bp and includes2888 bp respectively,the entire Exon Figure 1 2andA). Thethe 5first0-untranslated 20bp of the region proximal (50-UTR) region of of POMC Exon mRNA 2 (Figure includes 2B). The the remainingentire Exon sequence 1 and the of first Ex 20on bp2 encodes of the proximal a signal region peptide of Exonand the 2 (Figure first 18aa2B). Theof the remaining POMC precursor sequence (ofFigure Exon 2B) 2 encodes. A large a signalpart ofpeptide Exon 3 is and translated the first 18aato 223aa of the of POMCthe POMC precursor peptide (Figure and the2B). 3′ A-UTR large covers part aof 228bp Exon 3sequence is translated of the to 223aa3′ end of of the Exon POMC 3 (Figure peptide 2B) and. The the 3N0-UTR-terminal covers 26aa a 228-signal bp sequencepeptide of of the precursor30 end of ExonPOMC 3 (Figure protein2 B).is cleaved The N-terminal during maturation, 26aa-signal peptideand the ofremaining the precursor 241aa POMC region proteinis further is processedcleaved during into maturation,several peptides and the in remaininga tissue-specific