Encyclopedia of endocrine diseases

2835 Pages·2004·63.159 MB·English

by  Luciano Martini

ACTH (Adrenocorticotropic Hormone)
George Mastorakos
UniversityofAthens,Athens,Greece
Evangelia Zapanti
AlexandraHospital,Athens,Greece
Interestingly, only the first 18 amino acids beginning
Glossary with the NH -terminal amino acids of ACTH are
2
required for biological activity. In the brain, POMC
g0005 adrenocorticotropic hormone (ACTH) A 39-
isexpressedinthearcuatenucleusofthehypothalamus
amino-acid peptide hormone (MW 45,000) that is part
of the proopiomelanocortin precursor molecule. It andthenucleustractussolitariusofthecaudalmedulla.
controlsthe functionofthe adrenalcortex. In the brain, POMC generates a range of bioactive
peptides, including ACTH, b-endorphin, and a-, b-,
proopiomelanocortin (POMC) A precursor mol-
andg-MSH.b-Lipotropin,afragmentwith91amino
ecule (MW 28,500) that, in the anterior lobe of the
pituitary,isprocessedtoadrenocorticotropichormone acids,whichcontainsb-MSH(41-58),g-LPH(1-58),
andb-lipotropinandfurtherprocessedtob-endorphin, and b-endorphin, is secreted in equimolar quantities
an endogenousopioidpeptideof 31aminoacids. withACTH.Theendogenousopioidpeptidesa-,b-,
and g-endorphin are derived from POMC and are
composedofaminoacids61–76,61–91,and61–77of
b-LPH,respectively.
A
drenocorticotropin is the hypophyseal hormone that The biological effects of POMC-derived peptides
controlsthefunctionoftheadrenalcortex. arediverseandarelargelymediatedthroughmelano-
cortin (MC) receptors (R), five of which have been
described. MC1R, MC2R, and MC5R have estab-
lished roles in the pigmentation in the skin, adrenal
BIOCHEMISTRY
steroidogenesis, and thermoregulation, respectively.
Adrenocorticotropichormone(ACTH)isa39-amino- Proopiomelanocortin-derivedpeptidesarealsofound
p0010
acidpeptidehormone(MW45,000)thatispartofthe intheplacenta,pancreas,testes,andgastricantrum.
proopiomelanocortin (POMC) precursor molecule
(MW28,500).ThePMOCgeneislocatedonchromo-
PATHOLOGYAND EMBRYOLOGY
some2.Proopiomelanocortinisexpressedinthebrain,
skin,andimmunesystemandintheanteriorandinter- The synthesis and processing of POMC to ACTH
mediate lobes of the pituitary gland. In the anterior and to the other POMC derivatives are executed
lobe,POMCisprocessedtoACTHandb-lipotropin within the corticotroph cells of the anterior pituitary
(b-LPH), which is further processed to b-endorphin, lobe. This cell type was originally considered chro-
an endogenous opioid peptide of 31 amino acids mophobic and later was shown by light microscopic
(Fig.1).Intheintermediatelobe,ACTHisprocessed studiestobebasophilic(Fig.2).Corticotrophsrepre-
to a-melanocyte-stimulating hormone (a-MSH) sent15–20%ofadenohypophysealcells.Theembryo-
(ACTH 1-13) and corticotropin-like intermediate logical origin of corticotrophs is the intermediate
lobe peptide (CLIP) (ACTH 18-39). In species with lobe, but groups of cells migrate duringdevelopment
developed intermediate lobes (rat and sheep), these into regions of the anterior and posterior lobes.
fragments are secreted, whereas in humans they are Ultrastructuralstudieshaveshowndifferentmorphol-
normally found only during fetal life. The NH - ogiesinthesetwogroupsofcells,reflectingdifferences
2
terminal amino acids of ACTH are identical in all in the processing enzymes responsible for the pro-
species thus far studied, but there are species differ- duction of the above-mentioned hormones. The cells
ences in the COOH terminus of the molecule. in the anterior lobe appear irregularly shaped with
EncyclopediaofEndocrineDiseases,Volume1.(cid:1)2004ElsevierInc.Allrightsreserved. 25
26 ACTH(AdrenocorticotropicHormone)
POMC
N-terminal fragment ACTH β−Lipoprotein
γ−MSH β−MSH
ACTH β−Lipoprotein
α−MSH CLIP γ−Lipoprotein β−Endorphin
Figure 1 EnzymaticprocessofPOMCinthepituitary.
sparse secretory granules and poor staining, whereas MEASUREMENT OF ACTH
those of the intermediate and posterior lobes exhibit
Theradioimmunoassayforthemeasurementofplasma
dense granulation. In states of glucocorticoid excess
ACTHisahighlysensitiveandreliableassayforclin-
(endogenous or exogenous), corticotrophs undergo
ical use. Assays using other methodologies are also
degranulationandmicrotubularhyalinization,known
widelyemployed(i.e.,enzyme-linkedimmunosorbent
as Crooke’s hyaline degeneration. In adrenal insuffi-
assay, chemiluminescence). The basal morning con-
ciency, the corticotroph cells in the anterior lobe in-
centration of ACTH ranges from 9 to 80pg/ml. The
crease in number and the densely granulated cells of
episodic secretion of ACTH causes fluctuations in
the intermediate and posterior lobes decrease in
plasma ACTH and cortisol levels. ACTH secretion
number.
has a distinct diurnal rhythm, with peak levels in the
early morning and the lowest levels at approxi-
matelymidnight.TheinterpretationofACTHvalues
requires a simultaneous cortisol determination. Pro-
vided that adrenocortical function is intact, plasma
cortisol measurements, from a practical viewpoint,
are a reliable index of ACTH secretion. There are
otherassaysavailableformeasuringACTH(bioassays,
radioreceptor assays, cytochemical assays), but meas-
urement of ACTH by these techniques is performed
only for research purposes, because of complexity
and cost. The half-life of ACTH depends on the
assayusedforitsmeasurement.BioactiveACTHdis-
appearsfromthecirculationmorerapidly(half-lifeof
3–9 min) than does immunoreactive ACTH (half-life
of7–12min).
PHYSIOLOGY
Control of ACTH Secretion
The secretion of ACTH is controlled by an inherent
Figure 2 Corticotroph cells in the anterior pituitary, positively diurnalrhythmicity;itisaugmentedbynoxious stim-
stainedimmunohistochemicallywithabasophilicstain. uli that are neurally, hormonally, and biochemically
ACTH(AdrenocorticotropicHormone) 27
mediated,whichistermedstress(open-loopcompon- known about the effects of feeding schedule on
ent), and isinhibited byglucocorticoids (closed-loop, ACTH releasein humans.
negativefeedback).Innormalcircumstances,thedaily
secretion of ACTH and cortisol is episodic and vari- Open-Loop Control (Stress)
able. The highest burst of activity is observed in Theopen-loopcomponentofACTHcontrolmaybe
the early morning hours. Thereafter, the release of initiated by noxious stimuli of various sorts, all of
bothACTHandcortisoloccursonlyin7–15episodes whichrepresenttypesofphysical oremotional stress,
per day and the levels of both hormones gradually such as pain, fever, trauma, hypoglycemia, hypoxia,
decrease,reachinganadiratapproximatelymidnight. surgery, anxiety, and depression. All of these stimuli
stimulate the secretion of ACTH via the release of
Diurnal Rhythmicity CRH. Corticotropin-releasing hormone and AVP
Thebasisofthediurnalrhythmispoorlyunderstood. areprobablythetwomajorphysiologicsecretagogues
Thereisevidencefortheinvolvementofatleastthree of hypophyseal ACTH. Immunoreactive CRH is
factorsinthe regulation ofthediurnalrhythmicity of found in the human hypothalamus in the paraventri-
ACTH:(1)intrinsicrhythmicityofthesecretionofthe cular, supraoptic, and infundibular nuclei and also in
corticotropin-releasing factor (CRH) as well as vaso- the human thalamus, cortex, cerebellum, and pons.
pressin (AVP); (2) light–dark exposure; and (3) feed- However, most human CRH-secreting neurons are
ing times. Diurnal variation frequently disappears located in the anterior portion of the paraventricular
during periods of stress and depression and is also nucleusandtheirnerveendingsprojecttotheexternal
changedbyconditionsthataffectcortisolmetabolism layerofthemedianeminence,whereCRHisreleased
(liverdisease,chronicrenalfailure,alcoholism). into the portal hypophyseal circulation. The same
neuronal bodies in the paraventricular nucleus also
Intrinsic Rhythmicity of Hypothalamic CRH and AVP produce AVP. These AVP neurons are probably the
TestsfortheevaluationoftheCRHsecretionpattern most important in vasopressin control of ACTH re-
have shown a diurnal intrinsic rhythmicity that per- lease, but the major site of vasopressin neurons is the
sists even in hypophysectomized animals that are de- supraoptic nucleus. These vasopressin neurons are
prived of ACTH and glucocorticoid feedback. This usually of the magnocellular type and most of them
hypothalamic rhythmicity appears to be neuronal but project to the neural lobe.
not hormonal. On the other hand, the presence of There is strong evidence that both a- and
diurnalrhythmicityofACTHinwomenduringpreg- b-adrenergic stimuli, cytokines, angiotensin II, and
nancy when the increased circulating levels of pla- opiates are involved in the regulation of ACTH se-
centa-derived CRH do not show a nychthemeral cretion. During infection, autoimmune processes, or
rhythm strongly suggests that hypothalamic AVP trauma, a complex cascade of events ensues, charac-
secretion plays arole inthis diurnal regulation. terized by fever, circulation of cytokines, and alter-
ations in acute-phase proteins in plasma that are
Light–Dark Cycles important to initiate, propagate, and terminate host
Secretory episodes of ACTH increase between the defense mechanisms. In addition, it has been known
thirdandfifthhoursofsleepandpeakinthemorning for several decades that activation of the hypothal-
during the first several hours of wakefulness. This amic–pituitary–adrenal (HPA) axis occurs in parallel.
rhythm usually appears after the first year of life It has become apparent that several mediators of in-
but may not be established until the age of 8 years. flammation play a major role in this phenomenon.
Reversal of the normal asleep–awake patterns, as Among all cytokines, three [tumor necrosis factor a
occurs when an individual moves to a distant time (TNFa), interleukin-1 (IL-1), and interleukin-6 (IL-
zone, is followed by a corresponding change in the 6)] are responsible for most of the stimulation of the
diurnalpatternofACTHsecretionoverthecourseof HPA axis that is associated with the immune/inflam-
2 to 3weeks. matoryresponse.Thesethreecytokinesareproduced
at inflammatory sites and elsewhere in response to
Feeding Cycles inflammation. Tumor necrosis factor a, which has a
Experimentsinratshaveshownthatfeedingschedule tumoricidal activity and isresponsible for cachexia, is
is more important than the light–dark cycle in deter- the first to appear in the inflammatory cascade of the
miningtheglucocorticoiddiurnalsecretorypattern.It events and stimulates both IL-1 and IL-6; similarly,
appears that glucocorticoids tend to be released IL-1 stimulates both TNFa and IL-6. In contrast,
during fasting and decrease with feeding. Less is IL-6, which participates in a major fashion in the
28 ACTH(AdrenocorticotropicHormone)
acute-phasereaction,inhibitsthesecretionofbothof feedback, and (3) slow feedback, which is sensitive to
the other cytokines. All three inflammatory cytokines theabsolutecortisollevel.Increasedconcentrationsof
havebeenshowntoactivatetheHPAaxis,i.e.,ACTH glucocorticoidsacceleratetheprogressionfromfastto
secretioninvivo,aloneorinsynergywithoneanother. slow feedback. Both fast feedback and intermediate
This effect can be blocked significantly with CRH- feedback appear to be mediated by inhibition of the
neutralizing antibodies, glucocorticoids, and prosta- releaseoftheexistingCRHandACTHratherthanby
noid synthesis inhibitors. When administered to inhibition oftheirsynthesis.Slow feedback ischarac-
humans, both IL-1 and TNFa have significant tox- terized by decreased synthesis of ACTH, complete
icity, including fever, general malaise, and hypoten- suppression of POMC gene transcription, and a lack
sion, at the doses needed to activate the HPA axis. In of responsiveness of the corticotroph to the admin-
the past, it has been demonstrated that IL-6, with its istration of CRH. The last result is mediated by the
abilitytoinhibitthetwootherinflammatorycytokines direct inhibitory effect of cortisol on the pituitary
anditsmodesttoxicityinexperimentalanimals,wasa and there is evidence suggesting that this inhibitory
potentstimulatoroftheHPAaxisinhumans,causing effect of cortisol at the level of the pituitary consti-
an impressively marked and prolonged elevation of tutes the most important cortisol negative feedback
plasmaACTH andcortisol when administeredeither in the physiological regulation of ACTH secretion.
subcutaneously or intravenously. The elevations of Glucocorticoidsdecreasethehypothalamiccontentof
ACTH and cortisol attained after stimulation with CRH and AVP and also decrease AVP mRNA con-
IL-6 were well above those observed with maximal tent, but they have only a minimal effect on CRH
stimulatory doses of CRH, suggesting that parvocel- mRNA.Electrophysiologicalstudieshaveshownthat
lular AVP and other ACTH secretagogues were there are hypothalamic as well as extrahypothalamic
also stimulated by this cytokine. In a dose–response sites of cortisol feedback, which serve to suppress the
study, maximal levels of ACTH were seen at doses at releaseof CRH.
which no peripheral AVP levels were increased. At
higher doses, however, IL-6 stimulated peripheral
Action of ACTH
elevations of AVP, indicating that this cytokine
might also be able to activate magnocellular AVP- The adrenal cortex is the principal target organ for
secreting neurons. This suggested that IL-6 might ACTH.ACTHstimulatesthesynthesisandreleaseof
beinvolvedinthegenesisofthesyndromeofinappro- steroidsbybindingtohigh-affinityplasmamembrane
priate secretion of antidiuretic hormone, which is receptors of adrenocortical cells. The ACTH–recep-
observed in the course of infectious or inflammatory torinteractionthenactivatesadenylcyclaseandthere-
diseases or during trauma. It has been shown that fore stimulates the production of intracellular cyclic
IL-6,inpatientswithheadtrauma(anasepticinflam- AMP(cAMP).ThecAMPformedactivatesanumber
matory state) and a syndrome of inappropriate secre- of intracellular phosphoprotein kinases that mediate
tion of antidiuretic hormone, is quantitatively both acute and chronic effects on steroidogenesis.
correlated with AVP.
In addition to their hypothalamic effects, the in- Acute and Chronic Actions of ACTH
flammatory cytokines can apparently directly stimu- ACTHstimulatesthesynthesisandreleaseofcortisol
late pituitary ACTH and adrenal cortisol secretion. within2to3minbyincreasingfreecholesterolforma-
Thismayberelatedtothechronicityoftheelevation tionasaconsequenceofincreasedcholesterolesterase
of the inflammatory cytokines or may be a dose- activity and decreased cholesteryl ester synthetase
related phenomenon. It is noteworthy that IL-1 and activity. ACTH rapidly promotes the transport of
IL-6arethemselvesproducedintheanteriorpituitary cholesterol across the mitochondrial membranes, fa-
and adrenal glands, where they may have autocrine/ cilitates the binding of cholesterol to the cytochrome
paracrine effects. P450scc, and facilitates the release of newly synthe-
sized pregnenolone from the mitochondria. ACTH
Closed-Loop Feedback also stimulates the release of adrenal mineralocorti-
The negative feedback control of ACTH secretion is coids and androgens, as well as the release of various
mediated by cortisol, which exerts inhibitory effects intermediate products. Chronic actions of ACTH
on both the central nervous system and the pituitary. areexertedonbothadrenalarchitectureandsteroido-
Negative feedback occurs via three mechanisms: genesis. ACTH chronically stimulates low-density
(1) fast feedback, which is sensitive to changes in lipoprotein (LDL) uptake and metabolism and the
the levels of circulating cortisol, (2) intermediate synthesisoftheLDLreceptorandofotherfactors,so
ACTH(AdrenocorticotropicHormone) 29
ithastropiceffectsonallknownearlystepsinsteroi- Favrod-Coune,C.A.,Gaillard,R.C.,Langevin,H.,Jaquier,M.C.,
dogenesis. Chroniceffectsof ACTHon steroidogen- Doci,W.,andMuller,A.F.(1986).Anatomicallocalizationof
corticotropin-releasingactivityinthehumanbrain.LifeSci.39,
esisoccurmainlybypromotingthetranscriptionofthe
2475–2481.
genes that encode steroidogenic enzymes and other
Gionis, D., Ilias, I., Moustaki, M., et al. (2003). Hypothalamic–
factors. ACTH increases the transcription of the pituitary–adrenalaxisandinterleukin-6activityinchildrenwith
genes for P450scc, P450c17, P450c21, and P450c11 head trauma and syndromeof inappropriate secretion of anti-
and stimulates the accumulation of human P450scc diuretichormone.J.Pediatr.Endocr.Metab.16,49–54.
Grino, M., Dakine, N., Paulmyer-Lacroix, O., and Oliver, C.
mRNAandhumanP450sccactivity.Theexactmech-
(2001). Ontogeny of the hypothalamic–pituitary–adrenal axis.
anisms of ACTH stimulation of the side-chain cleav-
In ‘‘Adrenal Disorders’’ (A. N. Margioris and G. P. Chrousos,
age enzyme P450scc remain to be elucidated. ACTH eds.),pp.1–10.HumanaPress,Totowa,NJ.
promotes both adrenal cellular hypertrophy and Jefcoate, C. R., McNamara, B. C., and DeBartolomeis, M. S.
hyperplasia.ACTHatphysiologicconcentrationscan (1986).Controlofsteroidsynthesisinadrenalfasciculatacells.
Endocr.Res.12,315–350.
promotethesynthesisofinsulin-likegrowthfactor-II
Krieger,D.T.(1979).RhythmsinCRF,ACTHandcorticosteroids.
(IGF-II) and also the synthesis of basic fibroblast
In ‘‘Endocrine Rhythms’’ (D. T. Krieger, ed.), pp. 123–142.
growth factor and epidermal growth factor, which RavenPress,NewYork.
mayactwithIGF-IItostimulateadrenalgrowth. Malee,M.P.,andMellon,S.H.(1991).Zone-specificregulationof
twodistinctmessengerRNAsforP450c11(11/18-hydroxylase)
in the adrenals of pregnant and non-pregnant rats. Proc. Natl.
Acad.Sci.USA88,4731–4735.
See Also the Following Articles
Mastorakos,G.,Chrousos,G.P.,andWeber,J.S.(1993).Recom-
ACTH, a-MSH, and POMC, Evolution of . Adrenal binant interleukin-6 activates the hypothalamic–pituitary–
adrenal axis in humans. J. Clin. Endocrinol. Metab. 77,
Cortex, Anatomy . Adrenal Cortex, Physiology . Adrenal
1690–1694.
Suppression.CircadianRhythms:HormonalFacets.Cor-
Mesiano, S., Mellon, S. H., Gospodarowicz, D., DiBlasio, A. M.,
ticotropin-Releasing Hormone, Family of . Glucocorti-
andJaffe,R.B.(1991).Basicfibroblastgrowthfactorexpression
coids,Overview.StressandEndocrinePhysiology isregulatedbycorticotropininthehumanfetaladrenal:Amodel
for adrenal growth regulation. Proc. Natl. Acad. Sci. USA 88,
5428–5432.
Further Reading Miller, W. L., and Tyrell, J. B. (1995). The adrenal cortex. In
‘‘Endocrinology and Metabolism’’ (P. Felig, J. D. Baxter, and
Chrousos, G. P. (1995). The hypothalamic–pituitary–adrenal axis L. A. Frohman, eds.), International Edition, pp. 555–680.
andtheimmune/inflammatoryreaction.N.Engl.J.Med.332, McGrawHill,NewYork.
1351–1362. Smith,A.L.,andFunder,J.W.(1988).Proopiomelanocortinpro-
Desir,D.,VanCauter,E.,Fang,V.,etal.(1981).Effectsof‘‘jetlag’’ cessinginthepituitary,centralnervoussystem,andperipheral
onhormonalpatterns.I.Procedures,variationsintotalplasma tissues.Endocr.Rev9,159–179.
proteinsanddisruptionofadrenocorticotropin–cortisolperiod- Tanaka,K.,Nicholson,W.E.,andOrth,D.N.(1978).Thenature
icity.J.Clin.Endocrinol.Metab.52,628–641. oftheimmunoreactivelipotropinsinhumanplasmaandtissue
DiBlasio, A. M., Voutilainen, R., Jaffe, R. B., and Miller, W. L. extracts.J.Clin.Invest.62,94–104.
(1987). Hormonal regulation of mRNAs for P450scc (20,22 Whitfeld,P.L.,Seeburg,P. H.,andShine,J.(1982).Thehuman
desmolase)and (17a-hydroxylase/17,20lyase) incultured fetal proopiomelanocortin gene: Organization, sequence, and
adrenalcells.J.Clin.Endocrinol.Metab.65,170–175. interspersionwithrepetitiveDNA.DNA1,133–143.
ACTH, a-MSH, and POMC, Evolution of
Robert M. Dores and Phillip B. Danielson
UniversityofDenver,Denver,Colorado,UnitedStates
a-melanocyte-stimulating hormone (a-MSH) and
Glossary b-melanocyte-stimulating hormone (b-MSH), poly-
peptides characterized from the intermediate pituit-
adrenocorticotropin(ACTH) Ananteriorpituitary
ary. The fact that ACTH contained the complete
polypeptide hormone that induces the production of
cortisol bycells oftheadrenalcortex. sequence of a-MSH and that b-LPH contained the
complete sequence of b-MSH led to the hypothesis
g0015 b-lipotropin (b-LPH) A biosynthetic intermediate
that all of these polypeptides had a common origin.
derived from the proopiomelanocortin precursor that
Later immunocytochemical studies would show
contains the sequence of b-melanocyte-stimulating
hormone andb-endorphin. that ACTH-related immunoreactivity and b-LPH-
related immunoreactivity were colocalized in the
melanocortins Adrenocorticotropin, a-melanocyte-
corticotropic cells of the anterior pituitary, whereas
stimulating hormone (MSH), b-MSH, g-MSH, and
a-MSH-related immunoreactivity and b-MSH-
d-MSH.
related immunoreactivity were colocalized in the
g0010 a-melanocyte-stimulating hormone (a-MSH), melanotropic cells of the intermediate pituitary.
b-MSH, g-MSH, d-MSH Polypeptide hormones
From these observations, several research groups in
produced in the intermediate pituitary that share the
the 1970s arrived at two conclusions: (1) ACTH,
melanocortincoresequence HFRW.
b-LPH, a-MSH, and b-MSH must be derived from
proopiomelanocortin (POMC) The common pre-
a common precursor and (2) the common precursor
cursor for melanocyte-stimulating hormone-related
mustundergodifferentialposttranslationalprocessing
polypeptides andb-endorphin.
to yield distinct sets of end products in the anterior
pituitary and intermediate pituitary. The cloning and
characterization of proopiomelanocortin (POMC)
P mRNA from the bovine pituitary by Nakanishi and
roopiomelanocortin is the common precursor for the
colleagues in 1979 confirmed the common precursor
melanocortinsandb-endorphin.Thisgeneisexpressedincor-
ticotropiccellsoftheanteriorpituitaryandmelanotropiccells hypothesis. In addition, that study revealed the pres-
of the intermediate pituitary. As a result of differential post- ence of a third MSH sequence (g-MSH) in the pre-
translationalprocessing,thesetworegionsofthepituitarywill cursor. Since that time, the POMC gene has been
yield distinct sets of melanocortin-related and b-endorphin- analyzed in representative species from nearly every
relatedendproducts. majorgroupofvertebrate.Thisarticlefocusesonthe
changesthathaveoccurredinthePOMCgeneduring
the evolutionary radiation of the vertebrates.
INTRODUCTION
During the middle portion of the 20th century, prior ORGANIZATION OF POMC
to the implementation of immunocytochemistry and
IN TETRAPODS
subsequent molecular biology procedures to analyze
endocrine cells, several pituitary polypeptide hor- The organization of the POMC precursor is remark-
moneswerebiochemicallycharacterizedfromextracts ably conserved in tetrapods as diverse as amphibians
of the anterior and intermediate pituitary. These and mammals. Tetrapod POMC can serve as a good
analysesrevealedthesurprisingobservationthatadre- model to illustrate the distribution of biologically
nocorticotropin (ACTH) and b-lipotropin (b-LPH), active sequences and spacer regions within this
polypeptidescharacterizedfromtheanteriorpituitary, precursorandtooutlinethemajorissueswithrespect
shared the amino acid sequence motif HFRW with totheoriginandevolutionofthePOMCgenewithin
30 EncyclopediaofEndocrineDiseases,Volume1.(cid:1)2004ElsevierInc.Allrightsreserved.
ACTH,a-MSH,andPOMC,Evolutionof 31
Figure1 TheaminoacidsequenceofXenopuslaevisPOMC.Thededucedaminoacidsequenceforthepre-proformofPOMC
(AccessionNo.X59370)ispresented.Proposedendoproteolyticcleavagesitesaremarkedbyasterisks.MSHcoresequencesare
underlined.Theopioidcoresequenceforb-endorphinisY202G203G204F205.NTS,N-terminalsequence;JP,joiningpeptide.
the phylum Chordata. Tetrapod POMC can be melanocyte-stimulating activity at nonphysiological
divided into three major regions: the 16K fragment concentrations. However, studies on rats indicate
region, the ACTH region, and the b-LPH region that this peptide may be involved in regulating blood
(Fig. 1). The 16K fragment is located in the N- pressureatsitesoutsideofthecentralnervoussystem.
terminal region of POMC immediately following The g-MSH sequence is flanked by paired basic
the signal sequence. This region can be subdivided amino acids (R48K49 and K76R77), and these sites
into the N-terminal sequence (NTS), the g-MSH undergoendoproteolyticcleavageintheintermediate
sequence, and the joining peptide sequence. The pituitary but not in the anterior pituitary. In both
NTS (Q1–I47) contains four cysteine residues at pos- mammals and anuran amphibians, the R48K49 site is
itions 2, 8, 20, and 24. The number and location of a functional monobasic cleavage site. Hence, for the
thesecysteineresiduesrepresentafeaturecommonto Xenopus laevis POMC sequence presented in Fig. 1,
all gnathostome POMC sequences and undoubtedly the first residue in the g-MSH sequence is K49. The
playaroleininfluencingthethree-dimensionalstruc- reason for this particular cleavage event is not clear.
ture of the precursor. In vitro studies on developing Often,thepresenceofaprolineresidueC-terminalto
mammalian pituitary cells indicate that the NTS can a basic amino acid prevents the removal of the basic
serve as a maturation factor to promote the develop- amino acid. However, for the R48K49 sequence, the
ment of prolactin-producing cells. Studies have not position C-terminal to K49 is a tyrosine residue. In
been performed in vivo to verify this activity. fact,asseeninFig.2,thetyrosineresidueisconserved
However,itiscoincidentalthatinteleosts,vertebrates atthispositionintheg-MSHsequencesofvertebrates
in which the anterior pituitary cell types segregate asdiverseassharksandamphibians.Incontrasttothe
into zones, ACTH-producing cells are found in R48K49site,proteolyticcleavageatK76R77followsthe
close proximity to prolactin-producing cells. The conventional endoproteolytic mechanism and both
joining peptide region (E79–N111) is one of the most amino acids are removed. Many gnathostome g-
variable regions in POMC and is one of the spacer MSH sequences have a potential internal cleavage
regionsfoundinthisprecursor.Nofunctionhasbeen siteatR62R63thatcanbecleavedtoyieldanamidated
found for this sequence. Located between the NTS form of g-MSH that would correspondto K49–F60.
and the joining peptide is the sequence of g-MSH The ACTH region in the X. laevis POMC
(K49–Y75). g-MSH is one of three sequences within sequence extends from A113 to L152. ACTH is a
POMCthatcontainstheMSHcoresequenceHFRW. potent stimulator of cortisol production by adrenal
Bioassay studies indicate that g-MSH has weak cortical cells. This hormone plays a critical role in
32 ACTH,a-MSH,andPOMC,Evolutionof
Figure2 ComparisonofvariousvertebratePOMCsequences.ThededucedaminoacidsequencesforthePOMfromPOMC
inlamprey(Petromyzonmarinus;AccessionNo.55629)andthePOMCsequencesfordogfish(Squalusacanthias;AccessionNo.
AB017198),gar(Lepisosteusosseous;AccessionNo.U59910),sockeyesalmonPOMCA(Oncorhynchusnerka),Australianlungfish
(Neocerodatusforsteri;AccessionNo.AF141926),andXenopuslaevis(AccessionNo.X59370)arepresented.Sitesthatareidentical
inatleastfiveofthesixtaxaareshowninboldfacetype.MSHcoresequencesareunderlined.Theopioidcoresequenceislocated
atY319F322.
the hypothalamus–pituitary–adrenal axis in response An interesting featureof ACTH isthe presence of
to chronic stress. The ACTH sequence is flanked four basic amino acids located in the interior of the
by sets of paired basic amino acid proteolytic cleav- ACTH sequence (R128K129R130R131). In the inter-
age sites (K111R112 and R153R154). In the anterior mediate pituitary of all vertebrates, endoproteolytic
pituitary, both of these cleavage sites are removed to and exoproteolytic cleavage mechanisms remove
yield ACTH (1–39)as amajor end product. R128K129R130.However,thepresenceofP132,aresidue
ACTH,a-MSH,andPOMC,Evolutionof 33
found in all vertebrates at this position, apparently PHYLOGENETIC ANALYSIS OF
prevents cleavage atR131.The result ofthese proteo- POMC SEQUENCES
lyticcleavageeventsyieldsACTH(1–13)amide(A113–
V126)andcorticotropin-likeintermediatelobepeptide The POMC gene has been analyzed in a jawless fish,
(R131–L152) (CLIP) as products. ACTH(1–13) amide two cartilaginous fishes, several ray-finned fishes, two
willundergoN-terminalacetylationtoforma-MSH, lobe-finned fishes, several amphibians, and several
thesecondpolypeptidesequenceinamphibianPOMC mammals. Figure 2 provides a comparison of a few
thathastheMSHcoresequence(H119F120R121W122). representativespecies.Thesespecieswereselectedbe-
a-MSH is a potent stimulator of physiological color cause they represent five major taxonomic groups of
change in several species of amphibians and reptiles. vertebrates (i.e., jawless fish, cartilaginous fish, ray-
ThefunctionofCLIPisstillanenigma. finnedfishes,lobe-finnedfish,andtetrapods).Thejaw-
The final major region of the POMC precursor is less fish were well established over 500 million years
theb-LPHregion(Fig.1).LocatedintheC-terminal ago (mya) and are represented today by lamprey and
portion of POMC, this sequence has traditionally hagfish. In the lamprey, Petromyzon marinus, two dis-
been divided into the g-LPH sequence (E154–D199) tinct POMC genes are expressed. The POM form of
and the b-endorphin sequence (Y202–Q232). The POMC,ageneexpressedintheintermediatepituitary
former sequence contains the b-MSH sequence ofthisspecies,ispresentedinFig.2.Thejawedverte-
(N183–D199), the third polypeptide with a MSH core brates (gnathostomes) appear in the fossil record ap-
sequence (H190F191R192W193) in tetrapod POMC. proximately 420 mya and two distinct groups were
b-MSH has melanocyte-stimulating activity and established by 400 million years ago: the cartilaginous
appears to work in concert with a-MSH to promote fish,representedinFig.2bythedogfish,andthebony
physiologicalcolorchangeinamphibiansandreptiles. fish.Thebonyfishradiatedintotwomajorgroups:the
In all vertebrates in which MSH has been studied, ray-finned fish, represented by the gar and sockeye
b-MSH is an end product of the intermediate salmon, and the lobe-finned fish, represented by the
pituitary,but not of the anterior pituitary. Australianlungfish.Thelungfishlineagecanbetraced
The other major product derived from b-LPH is backinthefossilrecordto390mya.Approximately20
b-endorphin. This polypeptide is an endogenous millionyearslater,thefirsttetrapodswereclearlypre-
opiate-likechemicalsignalthatfunctionsasaninhibi- sentinthefossilrecord.X.laeviswasincludedinFig.2
tory neurotransmitter when released from neurons toprovide a representativetetrapod POMC sequence.
locatedinthecentralnervoussystem.Inthemamma- Tworay-finnedfishPOMCsequencesarealsoincluded
liananteriorpituitary,b-LPH isamajorendproduct in Fig. 2 to illustrate some unique features associated
andb-endorphinisaminorendproduct.Inthemam- with the radiation of the POMC gene in this group.
malian intermediate pituitary, just the opposite result The gar belongs to an older lineage of ray-finned fish
is observed. In this tissue, b-LPH serves as a biosyn- that can be traced in the fossil record back to the
thetic intermediate that is processed to yield N- Jurassicera.Thesockeyesalmonisateleost,arelatively
terminally acetylated, C-terminally truncated forms recentgroupofbonyfishthatfirstappearsinthefossil
of b-endorphin. The later peptides lack opiate recordduringtheCretaceousperiod.
receptor-binding activity. A striking feature of the sequences presented in
The organization of tetrapod POMC is interesting Fig. 2 is the presence of a-MSH-like, b-MSH-like,
foranumberofreasons.Thisprecursorcontainsthree andb-endorphinsequencesinalltaxa.Therehasbeen
polypeptidesequencesthathaveverydistinctfunctions considerable divergence of the POMC sequence in
(ACTH,a-MSH,andb-endorphin).Therepeatofthe vertebratesandwithouttheseconservedsitesitwould
MSHcoresequenceappearstobetheresultofaseriesof have been very difficult to align the agnathan POM
domainduplicationeventslikelyresultingfromunequal sequencetothegnathostomePOMCsequences.Even
crossover.ThisfeatureisnotuniquetoPOMC.Several with these conserved sites, it was still necessary to
neuropeptideprecursors,suchasproTRHorproenke- insert 11 gaps to facilitate the alignment of the
phalin, contain repeats of a biologically important sequences. The presence of a-MSH-like, b-MSH-
sequence. However, the presence of three MSH se- like sequences in the lamprey precursor indicates
quences in tetrapod POMC leads to the questions of thatthe POMCgene must havebeen inthe ancestral
whenthesesequencesappearedandwhichofthepoly- chordate. Indeed, this gene may have been in the
peptides was the ancestral MSH sequence. To address ancestral eucoelomates. Based on this data set, it is
these questions,a phylogenetic comparisonofPOMC not possible to ascertain when the a-MSH/b-MSH
sequencesisrequired. duplicationeventoccurred.Onehypothesiswouldbe
34 ACTH,a-MSH,andPOMC,Evolutionof
that the ACTH sequence appeared early in eucoelo- identical. For the b-endorphin region, 45% of the
mate evolution and that b-MSH is the result of the positionsareidenticalinalltaxa.Thispercentagerises
duplicationofthea-MSHsequence.Inthecaseofthe to67%whenallgnathostomefishsequencesarecom-
lamprey,nucleotideinsertionsoccurredinboththea- pared. Clearly, ACTH and b-endorphin must be
MSH-andtheb-MSH-codingregionsofthelamprey physiologicallyimportantinallvertebrates.
POM gene. The gnathostome a-MSH and b-MSH
sequences are highly conserved in the taxa presented
ORIGIN OF POMC
in Fig. 2. In addition, the b-endorphin region con-
tains a remarkable number of conserved sites in all POMC is a member of the opioid/orphanin gene
taxa. There must be selection pressure to retain cer- family that includes the proenkephalingene, the pro-
tain features of the b-endorphin sequence that is not dynorphingene,andtheproorphaningene.Aunifying
being exerted on other regions of the gene. feature of this family is the presence of at least one
A sequence that is conspicuously absent from the Y(F)GGF sequence in each precursor. To date,
lamprey POM sequence is g-MSH. Based on this ob- members of this gene family have not been found in
servation, it is reasonable to propose that the duplica- anyprokaryotesanditappearsthatthesegenesarenot
tioneventthatyieldedtheg-MSHsequencemusthave found inpseudocoelomatessuchasCaenorhabditis ele-
occurredintheancestralgnathostomes.Althoughag- gans. Hence, the gene family appears to have evolved
MSH-likesequencecanbedetectedindogfish,gar,and in the eucoelomates. Although POMC is clearly a
Australian lungfish POMC, this sequence is shorter member of this family because of the b-endorphin
thanthetetrapodg-MSHsequence.Inaddition,paired sequence,thepresenceofthemelanocortinsequences
basicproteolyticcleavagesitesarenotfoundC-terminal (ACTH,a-MSH,b-MSH,g-MSH,andd-MSH)isa
to the g-MSH sequence in the gar or lungfish se- feature that is unique to the POMC gene. Since
quences. In addition, the gar g-MSH-like sequence POMC is found in all vertebrate groups and perhaps
does not have an intact MSH core sequence and the iscommontoallchordates,theoriginofthemelano-
entire g-MSH sequence is absent in teleost POMC. cortin sequences may provide the key to deciphering
Apparentlyduring the radiation of the ray-finnedfish, the genesis of this opioid/orphanin gene family.
selection pressures favored the gradual degeneration
andeventuallossoftheg-MSHsequence. See Also the Following Articles
Whereas the presence of a-, b-, and g-MSH is a
ACTH(AdrenocorticotropicHormone).PituitaryTumors,
feature common to many tetrapods, the dogfish
ACTH-Secreting
POMCsequencehasafourthMSHsequence:d-MSH
(D223–P237;Fig.2).Thissequenceislocatedinalarge
insertion (V204–A242; Fig. 2) that appears to have oc- Further Reading
curredduringtheradiationofthecartilaginousfishand
Cone,R.D.(ed.)(2000).‘‘TheMelanocortinReceptors.’’Humana
henceislimitedtothisgroupofgnathostomes.
Press,Totowa,NJ.
Theuniquenessofthed-MSHsequenceisbalanced Danielson,P.B.,andDores,R.M.(1999).Molecularevolutionof
by the high degree of primary sequence conservation the opioid/orphanin gene family. Gen. Comp. Endocrinol. 113,
observedforACTHamongthegnathostometaxa.For 169–186.
Hadley,M.E.(ed.)(1988).‘‘TheMelanotropicPeptides,’’ Volumes
thegnathostomespeciespresentedinFig.2,66%ofthe
1,2,and3.CRCPress,BocaRaton,FL.
positionsareidenticalintheACTHsequence.Infact,
Norman, A. W., and Litwack, G. (1997). ‘‘Hormones,’’ 2nd ed.
88%ofthefirst25positionsingnathostomeACTHare AcademicPress,SanDiego,CA.
Addison’s Disease
see Adrenal Insufficiency