MSH receptors on mouse and human melanoma cells: receptor identification, analysis and quantification.
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Fowl model for vitiligo: genetic regulation on the fate of the melanocytes.
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Animals↗
Melanotropin as a potential regulator of pigment pattern formation in embryonic skin.
Frozen tissue sections of developing axolotl embryos were labeled by indirect immunofluorescence with anti-alpha-MSH. Anti-MSH immunoreactivity is first detectable in embryos when neural crest cells are migrating from the neural tube. Antibody labeling is visible around the lateral and ventral edges of the neural tube and in the embryonic ectoderm. As development progresses, the amount of labeling increases greatly, particularly in developing ectoderm. Western blots of soluble proteins extracted from various developmental stages of axolotl embryo ectoderm reveal that MSH activity is associated directly with several high molecular weight components that may be part of the embryonic extracellular matrix. Thus, we suggest that melanotropin activity is present in embryonic axolotl skin, is associated with the extracellular matrix, and is thereby in a position to play a supportive and/or directive role in the establishment of embryonic pigment patterns.
Ambystoma↗
Cerebrospinal fluid and plasma concentrations of POMC-related peptides in multiple sclerosis.
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Adult↗
Increased central immunoreactive beta-endorphin content in patients with Wernicke-Korsakoff syndrome and in alcoholics.
beta-endorphin, adrenocorticotrophin, and alpha-melanocyte stimulating hormone were measured by radioimmunoassay in three areas of human brain at necropsy in seven subjects with Wernicke-Korsakoff syndrome and in 52 controls. Thiamin concentration in six brain areas was also measured. Mamillary body beta-endorphin concentrations were significantly increased in those with the syndrome compared with controls, and those controls with high alcohol intake showed increased mamillary body beta-endorphin compared with controls with low alcohol intake. Brain thiamin concentration was similar in both groups, with the exception of the brainstem, where it was reduced in subjects with Wernicke-Korsakoff syndrome. Thalamic beta-endorphin in controls was inversely correlated with thiamin in frontal white matter, frontal cortex, parietal white matter and parietal cortex, while beta-endorphin in the hypothalamus of patients was inversely correlated with thiamin in frontal cortex, parietal white matter, thalamus and brainstem. These results suggest that there is a disturbance of the endorphinergic system in Wernicke-Korsakoff syndrome which may be related to alcohol intake.
Adrenocorticotropic Hormone↗
Stress-induced secretion of alpha-melanocyte-stimulating hormone is accompanied by a decrease in the activity of tuberohypophysial dopaminergic neurons.
The purpose of the present study was to examine the acute effects of stress on the secretion of alpha-melanocyte-stimulating hormone (alpha MSH) and the activity of tuberohypophysial dopamine (DA) neurons in female and male rats. The activity of tuberohypophysial DA neurons was estimated by measuring the accumulation of 3,4-dihydroxyphenylalanine (DOPA) following administration of the decarboxylase inhibitor NSD 1015, and the concentrations of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the intermediate and neural lobes of the posterior pituitary. The combination of brief (2 min) ether exposure followed by 30 min of supine restraint (immobilization in the supine position) decreased the rate of DOPA accumulation in the intermediate, but not in the neural lobe of both female and male rats. Similarly, brief ether exposure followed by 10, 20 or 30 min of supine restraint increased plasma alpha MSH concentrations and decreased DOPAC concentrations in the intermediate lobe of female and male rats. In the absence of ether, tube restraint (confinement in a cylindrical acrylic tube) increased alpha MSH secretion and decreased intermediate lobe DOPAC concentrations, whereas ether in the absence of physical restraint had no effect. These results suggest that the stress-induced activation of alpha MSH secretion in both female and male rats may be due, in part, to a decrease in the activity of tuberohypophysial DA neurons in the intermediate lobe of the posterior pituitary.
3,4-Dihydroxyphenylacetic Acid↗
Evidence that prolactin mediates the stimulatory effects of estrogen on tuberoinfundibular dopamine neurons in female rats.
The effects of ovariectomy and estrogen on prolactin secretion and/or the activity of tuberoinfundibular dopamine (TIDA) neurons were examined by either concurrently measuring concentrations of prolactin in plasma and 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence of female rats or by determining the rate of DA synthesis (accumulation of 3,4-dihydroxyphenylalanine (DOPA) after the administration of a decarboxylase inhibitor) in the median eminence. For comparison, concentrations of alpha-melanocyte-stimulating hormone (alpha MSH) in plasma and DOPAC in the intermediate lobe of the pituitary (an index of the activity of tuberohypophysial DA neurons) were also determined. Ovariectomy produced a time-dependent decrease in the accumulation of DOPA and the concentrations of DOPAC in the median eminence and prolactin in plasma with maximal effects occurring by 7 days. Estrogen administration to ovariectomized rats increased plasma prolactin and median eminence DOPAC concentrations to levels comparable to those in diestrous controls. In contrast, neither ovariectomy nor estrogen replacement altered the concentrations of alpha MSH in plasma or DOPAC in the intermediate lobe. Administration of the DA agonist bromocriptine blocked the ability of estrogen to increase plasma prolactin and median eminence DOPAC concentrations. Also, administration of antiserum to rat prolactin blocked the stimulatory action of estrogen on median eminence DOPAC concentrations. Taken together, these results indicate that the stimulatory effect of estrogen on the activity of TIDA neurons is mediated by prolactin.
3,4-Dihydroxyphenylacetic Acid↗
Suckling unmasks the stimulatory effect of dopamine on prolactin release: possible role for alpha-melanocyte-stimulating hormone as a mammotrope responsiveness factor.
Mounting evidence indicates that dopamine (DA) can stimulate as well as inhibit PRL release when given in appropriately low doses. In the present study, we investigated whether the suckling stimulus could influence this response. Pituitary cultures from suckled or nonsuckled rats were exposed to DA (10(-16) - 10(-6) M) during a reverse hemolytic plaque assay for PRL. Pituitary cells from nonsuckled rats exhibited only the inhibitory response to DA; exposure to high-dose DA (10(-6) M) reduced plaque area to 42.3 +/- 7.2% (mean +/- SEM) of control. A low dose of DA (10(-12) M) had no effect on PRL secretion (79.3 +/- 13.3% of control). In striking contrast, a brief suckling stimulus (10 min) rendered the mammotropes responsive to stimulation by low-dose DA (to 152.7 +/- 12.5% of control). Thus, suckling appears to be a requirement for expression of the stimulatory effect of DA in lactators. In a subsequent series of experiments we explored the possibility that a hypophysial factor, released during nursing, might mimic the effects of suckling on mammotrope responsiveness. Accordingly, we tested the effects of alpha-melanocyte-stimulating hormone (10(-7) M) and low-dose DA, alone or in combination, on pituitary cells from nonsuckled rats. Although neither agent alone had a dramatic effect on PRL secretion, concurrent administration of both of these significantly stimulated PRL release to 130.0 +/- 4.2% of control. Taken together, these results demonstrate that suckling renders mammotropes responsive to the stimulatory effects of DA. Moreover, our data indicate that alpha-melanocyte-stimulating hormone could function as a responsiveness factor in this phenomenon.
Animals↗
Alpha-melanocyte-stimulating hormone is a mammotrophic factor released by neurointermediate lobe cells after estrogen treatment.
When neurointermediate lobe (NIL) cells from ovariectomized rats are exposed to 17 beta-estradiol (E2) in vitro, they release a substance that rapidly induces the recruitment of additional PRL cells into the secretory pool. In the present study we tested the hypothesis that this mammotrophic factor is alpha MSH. Cocultures of anterior pituitary and NIL cells were incubated for 18 h, exposed to various treatments for 3 h, and then subjected to a reverse hemolytic plaque assay to quantify the percentage of all pituitary cells that released PRL. Combined exposure to E2 and NIL cells caused a significant increase in the fraction of anterior pituitary cells that released PRL, and the presence of TRH during the reverse hemolytic plaque assay did not affect the magnitude of the response. Treatment with dopamine (which inhibits alpha MSH release) reversed the recruitment of PRL secretors induced by E2 stimulation of NIL cells. Likewise, immunoneutralization with an antiserum directed against alpha MSH abolished the response. Furthermore, alpha MSH alone could substitute for E2 and NIL cells in evoking the recruitment response, whereas none of several other POMC-derived peptides had any consistent effect. Taken together, these results demonstrate that alpha MSH is a mammotrophic factor released by NIL cells in response to E2.
Animals↗
N-acetylation is required for the lactotrope recruitment activity of alpha-melanocyte-stimulating hormone and beta-endorphin.
Pituitary neurointermediate lobe (NIL) cells obtained from ovariectomized rats and exposed to 17 beta-estradiol in vitro have been shown to release an activity that induces acute recruitment of additional PRL-secreting cells. We have recently reported that alpha MSH, a major secretory product of the NIL, can substitute for this lactotrope-recruiting factor released by NIL cells in response to 17 beta-estradiol. beta-Endorphin (beta END) was not effective in this regard. Inasmuch as the degree of acetylation is critical to the activities of both of these molecules in other systems, we decided to assess its importance to lactotrope-recruiting activity in the present study. Anterior pituitary cells from ovariectomized rats were cultured overnight, exposed to various treatments for 3 h, and then subjected to a reverse hemolytic plaque assay for PRL. Exposure to mono- and diacetylated alpha MSH (N-ac-alpha MSH and di-ac-alpha MSH, respectively) or N-acetylated beta END (N-ac-beta END) caused a significant increase in the fraction of anterior pituitary cells that released PRL. In contrast, the Des-acetylated variants of both molecules had no lactotrope-recruiting activity. In a dose-response study, maximally effective doses of di-ac-alpha MSH and N-ac-beta END were equally effective with respect to their function as lactotrope-recruiting factors. Furthermore, the two peptides acted cooperatively when simultaneously applied in submaximal concentrations. Taken together, these results demonstrate that 1) N-acetylation is an essential requirement for the lactotrope-recruiting activity of alpha MSH and beta END in vitro; and 2) di-ac-alpha MSH and N-ac-beta END can act in a cooperative fashion to recruit additional cells into the PRL-secreting population.
Acetylation↗
Neurointermediate lobe peptides recruit prolactin-secreting cells exclusively within the central region of the adenohypophysis.
There is strong evidence that the hypophyseal neurointermediate lobe (NIL) mediates 17 beta-estradiol (E2)-induced PRL secretion in rats. Our laboratory has previously demonstrated that E2 stimulates NIL cells to release an activity that acutely increases the relative abundance of PRL-releasing cells in anterior pituitary (AP) cell cultures. We later found that secretory products of the NIL melanotropes, specifically the acetylated forms of alpha MSH and beta-endorphin (beta END), can account for this activity. Given that blood from the NIL initially perfuses the region of the AP proximal to the NIL, we tested the hypothesis that this specific area was preferentially responsive to the lactotrope recruitment activities. AP glands from ovariectomized rats were dissected into an inner zone, proximal to the NIL, and the remaining outer zone of the gland, then dispersed with trypsin. The resulting cells were cultured for 16 h, either alone or in coculture with NIL cells, and subsequently treated with medium alone (control) or with alpha MSH, beta END, or E2 (all at 1 x 10(-7) M) for 3 h and then subjected to reverse hemolytic plaque assays for PRL release. Under control conditions, the proportion of PRL-secreting cells was significantly greater in cultures from the outer zone of the AP than in those from the corresponding inner zone of the gland. Treatment of AP cells from the inner zone with alpha MSH, beta END, or the E2-induced NIL activity significantly increased the percentage of PRL secretors by about 8% of all AP cells. In contrast, the fraction of PRL-secreting cells in cultures from the outer zone was not affected by these treatments. We conclude that the recruitment of PRL-secreting cells in response to products of the NIL occurs only in that region of the AP proximal to the NIL.
Animals↗
Quantification of appetite-regulating hormones in children with hypothalamic and common obesity.
CONTEXT: The pathophysiology of hypothalamic obesity (HyOb) remains incompletely understood with no effective treatments. OBJECTIVE: We examined differences in appetite-regulating hormone concentrations between patients with HyOb, common obesity, and lean controls. DESIGN: Multiway cross-sectional case-control study of patients aged 2 through 19 years. SETTING: Two tertiary pediatric endocrinology centers. PATIENTS: Cases were obese (body mass index [BMI] > +2 SD score [SDS], "HyOb") and lean ("HyLean") patients with congenital (septo-optic dysplasia) or acquired (suprasellar brain tumor) hypothalamic disorders. Controls had common obesity ("Ob") or nonhypothalamic disorders and normal BMI ("Lean"). MAIN OUTCOME MEASURES: Relationships between the Dykens' Hyperphagia Questionnaire Score (DHQS), plasma or serum concentrations of leptin, insulin, α-melanocyte stimulating hormone (αMSH), brain-derived neurotrophic factor, oxytocin, acylated ghrelin, agouti-related peptide and copeptin, and BMI SDS. RESULTS: Dykens' Hyperphagia Questionnaire Score did not differ between HyOb and Ob patients (24 [17-34] vs 24 [18-31]) but correlated with BMI SDS in patients with hypothalamic disorders (P = 0.02). HyOb and Ob patients exhibited similarly increased anorexigens (insulin, leptin) and decreased orexigens (ghrelin, agouti-related peptide) compared to HyLean and Lean patients. The rate of BMI increase was independently associated with lower αMSH (β = -0.23 [-0.36 to -0.11], P = .0007) and ghrelin (β=-0.004 [-0.01 to 0.00], P = .001) concentrations, suggesting that αMSH replacement may be a therapeutic target for HyOb. HyLean patients demonstrated intermediate insulin responses to glucose compared to other subcohorts. CONCLUSION: In our cohort, patients with HyOb appeared indistinguishable from Ob in terms of their appetite and appetite-regulating neuroendocrine circuitry. Higher αMSH concentrations are associated with reduced weight gain and may be a target for therapeutic intervention.
alpha-MSH↗
Erythropoietin treatment and plasma levels of corticotropin-releasing hormone, delta sleep-inducing peptide and opioid peptides in hemodialysis patients.
An improvement of quality of life and objective brain function has been reported in patients receiving regular hemodialysis treatment (RDT) during treatment with recombinant human erythropoietin (r-huEPO). The mechanisms explaining this improvement are unknown. In this study the plasma levels of peptides known to be involved in CNS functions, namely corticotropin-releasing hormone, delta sleep-inducing peptide, beta-endorphin, methionine-enkephalin, beta-lipotropin and alpha-melanocyte-stimulating hormone, were measured by radioimmunoassay in seven stable RDT patients before the start of r-huEPO therapy and during 28 weeks' treatment. All patients responded with significantly increased hemoglobin concentrations. An improvement of well-being, state of mood and physical fitness was reported by the patients. There were no significant changes during the study in the plasma concentrations of any of the peptides measured. However, as the plasma levels of neuropeptides will not necessarily reflect the local concentrations in the vicinity of the nerve terminals, changes in the intracerebral concentrations of these peptides might occur in response to r-huEPO.
Adult↗
Quantification of MSH receptors on mouse melanoma tissue by receptor autoradiography.
MSH receptors on mouse melanoma tissue sections were quantified by receptor autoradiography, yielding results which were very similar to those obtained by a conventional receptor binding assay with isolated cells. In order to minimize non-specific binding, it proved to be crucial to use a radioactive monoiodinated MSH radioligand retaining full biological activity and to apply the binding conditions developed for isolated cells to the incubation of whole tissue sections. The displacement curves obtained after quantitative analysis of autoradiograms from tissue sections yielded a KD-value of the same order of magnitude (0.58 nM; average of n = 7 experiments) as those obtained in the normal binding assay with isolated cells (1.2 nM; average of n = 10 experiments). Similarly, receptor numbers per cell on tissue sections (14,700; n = 7) did not differ markedly from those determined with isolated cells (10,500; n = 10). These results demonstrate that receptor autoradiography can be applied to the quantification of peptide hormone receptors on peripheral tissues.
Animals↗
Demonstration of coexisting catecholamine (dopamine), amino acid (GABA), and peptide (NPY) involved in inhibition of melanotrope cell activity in Xenopus laevis: a quantitative ultrastructural, freeze-substitution immunocytochemical study.
This quantitative ultrastructural immunocytochemical study demonstrates the coexistence of a catecholamine [dopamine (DA)], an amino acid (GABA), and a neuropeptide [neuropeptide Y (NPY)] in axon varicosities innervating the pars intermedia of Xenopus laevis. The varicosities are assumed to control the pars intermedia melanotrope cells, which regulate skin color during the physiological process of background adaptation. Varicosity profiles appear to abut melanotrope cells and folliculostellate cells, star-shaped cells that intimately contact the melanotropes. All varicosity profiles contain two morphological types of vesicle. Monolabeling studies on routinely fixed and freeze-substituted tissues showed that the small, electron-lucent vesicles store GABA, whereas DA and NPY occur in larger, electron-dense ones. Double and triple labeling experiments, in which the degree of immunoreactivity was quantified per varicosity profile and per vesicle, led to the conclusion that (1) DA, GABA, and NPY coexist within almost all varicosity profiles and (2) DA and NPY are costored within electron-dense vesicles. Varicosity profiles that about melanotrope cells show a much higher ratio between the numbers of electron-lucent and electron-dense vesicles than varicosities contacting folliculostellate cells (15.8 and 3.3, respectively). This differential distribution is in line with the previous demonstration that, in contrast to GABA, NPY does not act directly on the melanotrope cells but indirectly, by controlling the activity of the folliculostellate cells.
Animals↗
Processing of adrenocorticotropin by two proteases in bovine intermediate lobe secretory vesicle membranes. A distinct acidic, tetrabasic residue-specific calcium-activated serine protease and a PC2-like enzyme.
Adrenocorticotropin (ACTH) is cleaved at the tetrabasic residue site, in pituitary intermediate lobe secretory vesicles, to yield ACTH1-17 and corticotropin-like intermediate lobe peptide (CLIP). ACTH1-17 is then converted to alpha-melanocyte-stimulating hormone (N-AcACTH1-13NH2) by first removing the Lys15-Lys16-Arg17 residues, followed by amidation of the COOH terminus and acetylation of the NH2 terminus. Bovine intermediate lobe secretory vesicle membranes were screened for proteolytic enzyme activity that will cleave the tetrabasic residues of ACTH. Two activities with pH optima of 5.0-6.0 and 7.5-8.0 were detected. The acidic, ACTH-converting enzyme cleaved ACTH1-39 at the tetrabasic residues between the Arg17-Arg18 bond to yield ACTH1-17 and CLIP, but did not cleave paired basic residues of pro-opiomelanocortin. This enzyme activity was characterized as a Ca(2+)-activated serine protease with unique specificity for the tetrabasic residues of ACTH1-39. The neutral activity preferentially generated ACTH1-17 and to a small extent ACTH1-16 from ACTH1-39 and ACTH1-24. This enzyme activity was Ca(2+)-dependent but was not inhibited by serine or aspartic protease inhibitors. The neutral activity was significantly immunodepleted by antiserum raised against bovine PC2/PC3, and together with specificity studies, suggests that the enzyme is a PC2-like serine protease. The pH optimum, distinct specificity for tetrabasic residues, and subcellular localization of the acidic ACTH-converting enzyme indicate a function of this enzyme in the in vivo conversion of ACTH1-39 to alpha-melanocyte-stimulating hormone in intermediate lobe secretory vesicles which have an acidic internal pH.
Adrenocorticotropic Hormone↗
Effects of synthetic ovine corticotropin-releasing hormone on plasma concentrations of immunoreactive adrenocorticotropin, alpha-melanocyte-stimulating hormone, and cortisol in dogs with naturally acquired adrenocortical insufficiency.
We evaluated the effect of ovine corticotropin-releasing hormone (CRH) on plasma immunoreactive (IR) concentrations of ACTH, alpha-melanocyte-stimulating hormone, and cortisol in 8 dogs with naturally acquired adrenocortical insufficiency. Of the 7 dogs with primary adrenal insufficiency, 6 had markedly high basal plasma IR-ACTH concentrations and exaggerated ACTH responses to CRH administration, whereas 1 dog that was receiving replacement doses of prednisone at the time of testing had normal basal IR-ACTH concentrations and a nearly normal response to CRH. In contrast, the 1 dog with secondary adrenocortical insufficiency had undetectable basal plasma IR-ACTH concentrations, which failed to increase after administration of CRH. Basal plasma alpha-melanocyte-stimulating hormone concentrations in the dogs with adrenal insufficiency were within normal range and were unaffected by CRH administration. In all 8 dogs with adrenal insufficiency, plasma cortisol concentrations were low and did not increase after administration of CRH. Therefore, stimulation with CRH produced 2 patterns of plasma IR-ACTH response when administered to dogs with naturally acquired adrenal insufficiency. Dogs with primary adrenal insufficiency had high basal plasma IR-ACTH concentrations and exaggerated responses to CRH, whereas the dog with secondary adrenal insufficiency had undetectable basal plasma concentrations of IR-ACTH that did not increase after stimulation with CRH.
Adrenal Cortex Hormones↗
Effects of temperature and neuroactive substances on hypothalamic neurones in vitro: possible implications for the induction of fever.
This paper reviews some of our findings which have shown the usefulness of in vitro methods in the study of hypothalamic neurones. (1) Membrane current analyses of dispersed neurones of the rat preoptic and anterior hypothalamus (POA) during thermal stimulation have revealed that warm-sensitive neurones are endowed with a non-inactivating Na+ channel having a high Q10 in the hyperthermic range (35-41 degrees C). (2) A brain slice study has shown that neurones in the organum vasculosum lamina terminalis (OVLT) region have much higher sensitivity to PGE2 than POA neurones. This provides further evidence of a critical role of the OVLT in translation of blood-borne cytokine signals into brain signals for fever induction. (3) Local application of IL-1 beta and IFN alpha altered the activity of thermosensitive (TS) neurones and glucose responsive (GR) neurones in vitro in an appropriate way to produce fever and anorexia. While the responses to IL-1 beta required the local release of prostaglandins, the responses to IFN alpha were found to be mediated by opioid receptor mechanisms. (4) The responses of POA TS neurones and VMH GR neurones to IL-1 beta but not those to IFN alpha, were reversibly blocked by alpha MSH, an endogenous antipyretic peptide. Thus, immune cytokines and their related neuroactive substances may affect hypothalamic TS and GR neurones thereby producing elaborately regulated changes in homeostatic functions such as thermoregulation (fever) and feeding (anorexia), which are considered as host defence responses.
Animals↗