Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The specific melanocortin receptors, MC3R and MC4R, are directly linked to metabolism and body weight control. These receptors are activated by the peptide hormone alpha-MSH and antagonized by the agouti-related protein (AGRP). Whereas alpha-MSH acts broadly on most members of the MCR family (with the exception of MC2R), AGRP is highly specific for only MC3R and MC4R. AGRP is a complex ligand of approximately 100 amino acids. Within AGRP, MCR recognition and antagonism is localized to a 34 residue, cysteine-rich domain that adopts an inhibitor cystine knot (ICK) fold. An oxidatively folded peptide corresponding to this domain, referred to as mini-AGRP, exhibits full antagonist function and selectivity for MC3R and MC4R. Here we investigate a series of chimera proteins based on the mini-AGRP scaffold. Amino acid sequences derived from peptide agonists are grafted into the mini-AGRP active loop, implicated in receptor recognition, with the goal of producing ICK based agonists specific for MC3R and MC4R. Several constructs indeed exhibited potent agonist activity; however, with all chimeras, receptor selectivity is significantly altered. Pharmacologic data indicate that the chimeras do not interact with MC receptors through native AGRP like contacts. A model to explain the data suggest that there is only partial overlap of the agonist versus antagonist binding surfaces within MC receptors. Moreover, accessibility to the binding pocket is highly receptor specific with MC3R being the least tolerant of ligand alterations.
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PMID:Chimeras of the agouti-related protein: insights into agonist and antagonist selectivity of melanocortin receptors. 1600 63

The action of the peptide hormone adrenocorticotropin (ACTH) to stimulate glucocorticoid production by the adrenal gland is an essential physiologic process, yet is dependent on a single unique genetic component--the ACTH receptor or melanocortin 2 receptor. Genetic defects that cause abnormalities in this receptor or in a protein required for its expression at the cell surface result in a potentially fatal disease (familial glucocorticoid deficiency). Overexpression of this receptor or inability to desensitize it is found in adrenal adenomas or hyperplasia associated with glucocorticoid overproduction (Cushing syndrome). These disorders are uncommon, but there are considerable data to show that the hypothalamo-pituitary-adrenal axis is overactive, or in some circumstances underactive, in more common situations including depressive illness and septic shock. The origin of these latter disturbances is undoubtedly complex and multifactorial, but there is good evidence that a component of this phenomenon is an altered responsiveness of the ACTH receptor to ACTH. Understanding the basis of ACTH responsiveness might, therefore, contribute to the understanding of disorders such as these and perhaps enable the hypothalamo-pituitary-adrenal axis to be manipulated beneficially in these circumstances.
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PMID:Mechanisms of disease: the adrenocorticotropin receptor and disease. 1693 99

Inherited adrenocorticotropin (ACTH) resistance diseases are rare and include triple A syndrome and familial glucocorticoid deficiency (FGD). These conditions show genetic heterogeneity, i.e., the identical clinical phenotype may result from defects in more than one gene. Clinically, FGD is characterized only by ACTH resistance, while the triple A syndrome exhibits a variety of additional clinical features. FGD is caused by mutations in the ACTH receptor (melanocortin 2 receptor, MC2R) and the recently identified melanocortin 2 receptor accessory protein (MRAP) genes. In addition, linkage to a locus on chromosome 8 has been demonstrated. The identification of further genes in ACTH resistance syndromes may reveal novel aspects of MC2R signalling and trafficking. This review will summarize the clinical, biochemical and genetic aspects of these rare but informative diseases.
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PMID:The genetics of ACTH resistance syndromes. 1716 31

The hypothalamic-pituitary-adrenal (HPA) axis is activated by stress. This involves the production of corticotropin releasing hormone (CRH) with the subsequent release of proopiomelanocortin (POMC) peptides, of which adrenocorticotropin hormone (ACTH) is most important. Although the skin has the capacity to produce CRH and POMC peptides, the immunomodulatory roles of ACTH in skin are yet unknown. IL-18 has been known to affect cells involved in the inflammatory response. In this study, we aimed to identify the regulatory effect of ACTH on IL-18 expression of skin keratinocytes. Exposure of HaCaT cells to ACTH stimulated formation of IL-18 mRNA transcript and its protein products in a dose-dependent manner. Furthermore, we suggest that ACTH-induced IL-18 production is via the caspase-1 activation pathway, as IL-18 production induced by ACTH could be suppressed by caspase-1 inhibitor, and ACTH could increase caspase-1 activity. The effect of ACTH on IL-18 production was blocked by specific inhibitors of p38 kinase (SB203580) or extracellular signal-regulated kinase (ERK) (PD98059). In addition, ACTH-induced rapid phosphorylation of p38 kinase and ERK, and ACTH signaling occurred via melanocortin receptor 1 (MC1R) and receptor 2 (MC2R). These results suggest that ACTH stimulates IL-18 expression in human keratinocytes, which provides an insight into the interaction between ACTH and inflammatory mediators.
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PMID:Adrenocorticotropin hormone stimulates interleukin-18 expression in human HaCaT keratinocytes. 1750 22

Melanocortin receptors have been implicated in the confounding factors of cardiovascular diseases such as obesity, insulin resistance and salt-sensitive hypertension. The aim of this study was determine how increased dietary salt intake affects the expression profiles of melanocortin system genes in relevant endocrine tissues. Total RNA was isolated from the pituitary and adrenal glands of Wistar Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SP-SHR) and subjected to real-time PCR analysis. Expression levels of pro-opiomelanocortin (POMC), POMC processing enzymes prohormone convertases 1 and 2 (PC1/PC2), melanocortin 3 receptor (MC3R) and melanocortin 5 receptor (MC5R) were not significantly affected by high dietary salt intake in either WKY or SP-SHR tissues. Consistent with known endocrine relationship between the pituitary and adrenal glands, the expression levels of the ACTH receptor, MC2R, were five orders of magnitude higher in adrenal tissues whereas those of POMC were three orders of magnitude higher in the pituitary. MC3R, PC1 and PC2 transcripts were expressed at similar levels in both tissues while MC5R was expressed at a higher level in the adrenal tissues. These results are therefore inconsistent with an endocrine pathway that involves pituitary derived gamma-MSH modulating adrenal function in response to high dietary salt intake.
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PMID:Prevalence of melanocortin system transcripts in rat salt homeostasis endocrine tissues. 1753 Nov 55

The processed products of the proopiomelanocortin gene (ACTH, alpha-MSH, beta-MSH, gamma-MSH, etc.) interact with five melanocortin receptors, the MC1R, MC2R, MC3R, MC4R, and MC5R to modulate and control many important biological functions crucial for good health both peripherally (as hormones) and centrally (as neurotransmitters). Pivotal biological functions include pigmentation, adrenal function, response to stress, fear/flight, energy homeostasis, feeding behavior, sexual function and motivation, pain, immune response, and many others, and are believed to be involved in many disease states including pigmentary disorders, adrenal disorders, obesity, anorexia, prolonged and neuropathic pain, inflammatory response, etc. The melanocortin-3 receptor (MC3R) is found primarily in the brain and spinal cord and also in the periphery, and its biological functions are still not well understood. Here we review some of the biological functions attributed to the MC3R, and then examine in more detail efforts to design and synthesize ligands that are potent and selective for the MC3R, which might help resolve the many questions still remaining about its function. Though some progress has been made, there is still much to be done in this critical area.
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PMID:Design, synthesis and biological evaluation of ligands selective for the melanocortin-3 receptor. 1758 28

The adrenocorticotropin (ACTH) receptor (melanocortin 2 receptor, or MC2R) is the smallest G-protein-coupled receptor that, when activated by the peptide hormone ACTH, stimulates cAMP production and adrenal steroidogenesis. Receptor expression is dependent on a specific membrane trafficking process involving an accessory protein (melanocortin 2 receptor accessory protein, or MRAP) and other unidentified components. In an attempt to discover novel receptor interacting proteins, the C-terminal tail of the MC2R was used to screen a mouse adrenal Y6 cell cDNA library using the bacterial two-hybrid system. This identified the nucleoporin Nup 50 (Npap60) as the major full-length interacting protein. Interaction was confirmed by a GST pulldown assay and by coimmunoprecipitation in human H295R cells (which express both proteins endogenously). Deletion analysis identified the region between residues 143 and 466 in Nup50 as being required for interaction with the MC2R. Stimulation of H295R cells with ACTH (10(-6) M) was followed by a gradual translocation of the Nup50-MC2R complex from the membrane to the nucleus after 30 min. This time course is most consistent with MC2R internalization dynamics and may suggest a novel role for Nup50.
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PMID:Interaction of the melanocortin 2 receptor with nucleoporin 50: evidence for a novel pathway between a G-protein-coupled receptor and the nucleus. 1762 72

As gestation progresses, human fetal adrenals (HFA) initiate the production of cortisol, which increases placental corticotropin-releasing hormone (CRH) biosynthesis. While adrenocorticotrophic hormone (ACTH) is important for the onset of cortisol production, the late gestational surge in cortisol production occurs despite falling ACTH levels in the fetal circulation. The authors determine if CRH directly regulates the expression of the ACTH receptor (ACTHR) in HFA definitive/transitional zone (DZ/TZ) cells. DZ/TZ cells isolated from midgestation HFA were cultured before treatment with 0.01 nM to 100 nM CRH or ACTH. Cortisol was measured by radioimmunoassay. Real-time reverse-transcriptase polymerase chain reaction was used to measure ACTHR mRNA. Whole-cell ACTH binding studies were performed using I(125) (Tyr-23) ACTH. CRH produced a dose-dependent rise in cortisol production and caused a time-dependent increase in ACTHR mRNA levels between 12 and 24 hours. As little as 0.1 nM CRH induced ACTHR transcript by 12-fold at 24 hours. Together with ACTH 0.01 nM, 0.03 or 0.1 nM CRH increased ACTHR expression more than ACTH alone. Binding assays demonstrated a 3.5-fold increase in ACTHR protein at 48 hours with combined CRH and ACTH treatment. Physiologic levels of CRH seen in the late-gestation fetus stimulate DZ/TZ ACTHR expression. Since placental CRH production increases strikingly near the end of gestation, the authors suggest that CRH-induced ACTH receptor expression may increase TZ responsiveness to circulating ACTH and contribute to the late gestational rise in cortisol secretion by the HFA, participating in an endocrine cascade that is involved in fetal organ maturation and potentially in the timing of human parturition.
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PMID:The regulation of adrenocorticotrophic hormone receptor by corticotropin-releasing hormone in human fetal adrenal definitive/transitional zone cells. 1795 86

The network regulating human adrenal development is complex. Studies of patients with adrenal insufficiency due to gene mutations established a central role for transcription factors GLI3, SF1 and DAX1 in the initial steps of adrenal formation. Adrenal differentiation seems to depend on adrenocorticotropic hormone (ACTH) stimulation and signalling, including biosynthesis and action of POMC, PC1, TPIT, MC2R, MRAP and ALADIN, all of which cause adrenocortical hypoplasia when mutated in humans. Studies of knockout mice revealed many more factors involved in adrenal development; however, in contrast to rodents, in humans several of those factors had no adrenal phenotype when mutated (e.g. WT1, WNT4) or, alternatively, human mutations have not (yet) been identified. Tissue profiling of fetal and adult adrenals suggested 69 genes involved in adrenal development. Among them were genes coding for steroidogenic enzymes, transcription and growth factors, signalling molecules, regulators of cell cycle and angiogenesis, and extracellular matrix proteins; however, the exact role of most of them remains to be elucidated.
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PMID:Adrenal gland development and defects. 1827 81

Tritium-labeled synthetic fragments of human adrenocorticotropic hormone (ACTH) [3H]ACTH (11-24) and [3H]ACTH (15-18) with a specific activity of 22 and 26 Ci/mmol, respectively, were obtained. It was found that [3H]ACTH (11-24) binds to membranes of the rat adrenal cortex with high affinity and high specificity (Kd 1.8 +/- 0.1 nM). Twenty nine fragments of ACTH (11-24) were synthesized, and their ability to inhibit the specific binding of [3H]ACTH (11-24) to adrenocortical membranes was investigated. The shortest active peptide was found to be an ACTH fragment (15-18) (KKRR) (Ki 2.3 +/- 0.2 nM), whose [3H] labeled derivative binds to rat adrenocortical membranes (Kd 2.1 +/- 0.1 nM) with a high affinity. The specific binding of [3H]ACTH-(15-18) was inhibited by 100% by unlabeled ACTH (11-24) (Ki 2.0 +/- 0.1 nM). ACTH (15-18) in the concentration range of 1-1000 nM did not affect the adenylate cyclase activity of adrenocortical membranes and, therefore, is an antagonist of the ACTH receptor.
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PMID:[Synthetic peptide KKRR corresponding to the human ACTH fragment 15-18 is an antagonist of the ACTH receptor]. 1836 34


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