Endocrinology Basic and Clinical Principles - part 4 pptx

Chapter 8 / Neuroendocrine–Immune Interface 123 initiating factors and their regulation will provide targets for novel therapies. SELECTED READINGS Buckingham JC, Cowell A-M, Gillies G, Herbison AE, Steel JH. The neuroendocrine system: anatomy, physiology and responses to stress. In: Buckingham JC, Cowell A-M, Gillies G, eds. Stress, Stress Hormones and the Immune System. Chichester, UK: John Wiley & Sons, 1997:9–47. Chikanza IC. Perturbations of arginine vasopressin secretion during inflammatory stress. Pathophysiologic implications. Ann NY Acad Sci 2000;917:825–834. Elenkov IJ. Systemic stress-induced Th2 shift and its clinical implications. Int Rev Neurobiol 2002;52:163–186. Harbuz M. Neuroendocrinology of autoimmunity. Int Rev Neurobiol 2002;52:133–161. Harbuz MS, Jessop DS. Is there a defect in cortisol production in rheumatoid arthritis? Rheumatology 1999;38:298–302. Harbuz MS, Jessop DS. Stress and inflammatory disease: widening roles for serotonin and substance P. Stress 2001;4:57–70. Li XF, Mitchell JC, Wood S, Coen CW, Lightman SL, O’Byrne KT. The effect of oestradiol and progesterone on hypoglycaemic stress-induced suppression of pulsatile luteinising hormone release and on corticotropin releasing hormone mRNA expres- sion in the rat. J Neuroendocrinol 2003;15:468–476. Lightman SL, Windle RJ, Ma X-M, Harbuz MS, Shanks N, Julian MD, Wood SA, Kershaw YM, Ingram CD. Dynamic control of HPA function and its contribution to adaptive plasticity of the stress response. In: Yamashita Y, et al., eds. Control Mecha- nisms of Stress and Emotion: Neuroendocrine-Based Studies. Amsterdam, The Netherlands: Elsevier, 1999:111–125. Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 1984;5:25–44. Tilders FJ, Schmidt ED, Hoogendijk WJ, Swaab DF. Delayed ef- fects of stress and immune activation. Baillieres Best Pract Res Clin Endocrinol Metab 1999;13:523–540. Chapter 9 / Insect Hormones 125 INSECTS/PLANTS/COMPARATIVE PART III 126 Part III / Insects / Plants / Comparative Chapter 9 / Insect Hormones 127 127 From: Endocrinology: Basic and Clinical Principles, Second Edition (S. Melmed and P. M. Conn, eds.) © Humana Press Inc., Totowa, NJ 9 Insect Hormones Lawrence I. Gilbert, PhD CONTENTS INTRODUCTION PTTH AND PROTHORACIC GLAND ACTIVATION ECDYSTEROIDS JUVENILE HORMONES CONCLUSION erpillars) of the gypsy moth, demonstrated that the insect brain released a substance (hormone) that controls insect molting, i.e., the secretion of a new and larger cuticle, to allow growth, and the digestion and shedding of the old cuticle (ecdysis). When the brain was extir- pated 10 d or more after the final larval–larval molt, pupation ensued, and brainless but otherwise normal moths emerged. If brain extirpation occurred <10 d after the last larval molt, the larvae failed to metamorphose to the pupal stage, although they survived for weeks. These and other studies led Kopec´ to conclude that the brain liberated some substance into the hemolymph (blood) that is essential for the larval-pupal molt and that it is released about 10 d after the last larval molt. This was the cornerstone of the field of neuroendocrinology. In the 1930s and 1940s, the giants of the field extended research on this brain factor, and the source of the factor was shown to be specific protocerebral neurosecretory cells. We now know that the brain factor acts on glands in the prothorax of the insect to elicit synthesis and secretion of a steroidal prohormone, an ecdysteroid, that is ultimately responsible for eliciting the molting process. The current name for this neurohormone is prothoracicotropic hormone (PTTH) (Fig. 1). On the basis of subsequent microsurgical studies, it was shown that glands attached to the brain, the corpora allata, were the source of a hormone (juvenile hormone [JH]) that controls the quality of the molt, i.e., whether 1. INTRODUCTION Recent estimates place the number of insect species at 2–20 million, more by far than the total of all other animals and plants on Earth. Although insects affect the human condition in a variety of ways, primarily as pol- linators, competitors for agricultural products, and vec- tors of disease, their sheer diversity and numbers make this class of arthropods worthy of study. Indeed, insects have become the model of choice for a variety of research endeavors in genetics, biochemistry, developmental biology, endocrinology, and so forth. Because they are encased in a semirigid exoskeleton (cuticle), insects and other arthropods must shed this cuticle periodically (molt) in order to grow and undergo metamorphosis. Although insect molting and metamorphosis have been scrutinized since the time of Aristotle, the exact control mechanisms have remained elusive. How- ever, research on insect hormones has contributed significantly to the general field of endocrinology. The now accepted dogma that the nervous system not only controls target organs via action potentials and neurotransmitters, but is also, in a sense, an endocrine system (hence, the term neuroendocrinology) was first conceptualized on the basis of data derived from studies on insect development. It was more than eight decades ago that Stefen Kopec´ (1922), working on larvae (cat- 128 Part III / Insects / Plants / Comparative it be larval–larval, larval–pupal, or pupal–adult. Its role is to favor the synthesis of larval (juvenile) structures and inhibit differentiation (metamorphosis) to the pupal and/or adult stages. Although the action of JH is con- nected to that of the molting hormone and it therefore does not, in a sense, act as an independent agent in controlling growth processes, it does act alone in many adult insects as a gonadotropic hormone. Thus, the three major glands controlling insect growth and development are the brain, prothoracic glands, and corpora allata, their respective secretions being a neuropeptide, a steroid, and sesquiterpenoid compounds (Fig. 2). Fig. 1. Endocrine control of metamorphosis. Most of the data contributing to this scheme were derived from studies on silkworms and the tobacco hornworm, Manduca sexta, although the scheme applies to all insects in a general sense. Note that in the case of Manduca, JH acid rather than JH is released from the corpus allatum toward the end of the last larval stage. Chapter 9 / Insect Hormones 129 Figure 1 is a generalized scheme for the Lepidop- tera (moths and butterflies) and the details may not per- tain to all insects. Specific neurosecretory cells (the prothoracicotropes) synthesize PTTH as a prohormone that is cleaved to the true PTTH as it is transported along the axons to the corpora allata, where it is stored in axon endings and ultimately released into the hemolymph. Once released, PTTH acts on the prothoracic glands to Fig. 2. Hormones and related molecules that play critical roles in control of molting and metamorphosis. (A) The structure of Bombyx PTTH. The upper diagram indicates the predicted organization of the initial translation product. The lower diagram shows the location of inter- and intracellular disulfide bonds. (B) Structure of cholesterol and some major ecdysteroids. (C) Structure of various JHs and methyl farnesoate. JH I and JH II are almost entirely restricted to the Lepidoptera, JHB 3 to the cyclorraphan Diptera, whereas JH III is ubiquitous in insects. 130 Part III / Insects / Plants / Comparative stimulate ecdysteroid synthesis. In the Lepidoptera, this stimulation results in the enhanced biosynthesis of 3-dehydroecdysone (3dE), which is converted into ecdysone (E) by a hemolymph ketoreductase and from that into 20-hydroxyecdysone (20E) in target cells, 20E being the principal molting hormone of insects. Additionally, as Fig. 1 notes, the corpora allata synthesize and secrete JH, which is bound to a hemolymph- binding protein (JHBP), transported to target tissues, and acts in concert with 20E to determine the quality of the molt. Although this process typifies the endocrine control of molting in most insects, the exact molecular mechanisms are conjectural, although great strides have been made in recent years and are the subject of the remainder of this chapter. 2. PTTH AND PROTHORACIC GLAND ACTIVATION 2.1. Chemistry and Role Almost all studies on PTTH action have been per- formed on larvae and pupae of the tobacco hornworm, Manduca sexta. This PTTH structure, as well as that of four other lepidopteran PTTHs, has been elucidated by direct sequencing or by deducing the structure after having cloned the gene. The first of these was the PTTH of the commercial silkworm, Bombyx mori. After more than 30 yr of study using several million Bombyx brains, Ishizaki and Suzuki (1992) purified and characterized the Bombyx PTTH (Fig. 2) and showed that it is synthe- sized as a prohormone of 224 amino acids and then cleaved to form the mature neurohormone, a homodimer (approx 26 kDa) containing inter- and intramonomer disulfide binds, the latter requisite for hormone activity. The Bombyx PTTH antibody reacts with putative prothoracicotropes in a variety of insects, including Manduca and Drosophila, as judged by immunocy- tochemical and immunogold analyses, but it is physi- ologically inactive in these species. Thus, there is likely high specificity in the epitopes of the PTTH neuropeptide that are required for interaction with a putative cell membrane receptor in the target glands (i.e., the prothoracic glands). Correlations have been reported between PTTH levels in the hemolymph and the molting hormone titer for both Manduca and Bombyx and, in both cases, reflect subsequent increases in the ecdysteroid titer. In Manduca, there are two PTTH peaks during the fifth (final) larval stage as well as two ecdysteroid surges. The first is responsible for a small increase in ecdysteroid titer at about d 3.5 of the 9-d fifth instar (stage) when the JH titer is at its nadir and also for a change in commitment (reprogramming), so that when challenged by a larger ecdysteroid surge 4 d later, target cells respond by synthesizing pupal rather than larval structures. Thus, these two ecdysteriod (and PTTH) peaks are primarily responsible for metamorphosis, and they must be elicited in a very precise manner in the absence of JH. Indeed, the precision of the molting process has contributed significantly to the success enjoyed by insects on this planet during the past half billion years. The prothoracicotropes apparently receive, directly or indirectly, information from the insect’s external (photoperiod, temperature) and internal environment (state of nutrition), and when the appropriate conditions are met, they release PTTH from their termini in the corpus allatum. How and where these influences are sensed and then “transmitted” to the neurons that synthesize PTTH is not known. 2.2. Action via Second-Messenger Systems The only confirmed targets of PTTH are the paired prothoracic glands, which have been well studied in Manduca, each gland composed of about 220 mono- typic cells surrounded by a basal lamina. Although no candidate PTTH receptor(s) has yet been reported in the prothoracic glands of any insect, the PTTH-prothoracic gland axis has many similarities to vertebrate steroid hormone–producing pathways, such as the adrenocorti- cotropic hormone (ACTH)-adrenal gland system. By analogy, it is probable that PTTH binds to a receptor that spans the plasma membrane multiple times, contains an extracellular ligand-binding domain, and has an intracellular domain that binds G protein heterotrimers. PTTH stimulates increased ecdysteroid production in the prothoracic glands via a cascade of events that has yet to be elucidated completely (Fig. 3). Studies in the 1960s revealed a correlation between circulating ecdysteroid titers and adenylate cyclase activity in the prothoracic gland, suggesting a role for cyclic adenosine monophosphate (cAMP), and also that at some developmental periods a cAMP-independent pathway might be involved. In the Manduca prothoracic gland, calcium is clearly pivotal in the response to PTTH. Glands incubated in Ca 2+ -free medium with a calcium chelator or a calcium channel blocker exhibit a greatly attenuated production of cAMP and ecdysteroids in response to PTTH. More recent studies have impli- cated the mobilization of internal as well as external Ca 2+ stores in the PTTH response and have demonstrated a striking rise in the Ca 2+ levels of prothoracic gland cells within a few seconds of PTTH administra- tion in vitro. Composite observations suggest that PTTH-dependent cAMP production by prothoracic glands is gener- ated by a Ca 2+ -calmodulin-sensitive adenylate cyclase. Chapter 9 / Insect Hormones 131 The interaction between calmodulin and G protein (presumably G sα ) is complicated and varies during the final instar. In the first half of this period, calmodulin activates prothoracic gland adenylate cyclase and facilitates G protein activation of adenylate cyclase. Subsequently, prothoracic gland G protein activation of adenylate cyclase is refractory to the presence of calmodulin in such assays. Calcium still apparently plays a role in the PTTH transductory cascade after the first half of the fifth instar, since incubation of pupal glands in Ca 2+ - free medium inhibits PTTH-stimulated ecdysteroidogenesis, and higher levels of Ca 2+ -calmodulin can still activate adenylate cyclase in prothoracic gland membrane preparations. Regardless of the complicated, developmentally dynamic relationships among calcium, calmodulin, G proteins, and adenylate cyclase, it is clear that PTTH elicits increased cAMP formation in prothoracic glands leading to activation of a cAMP-dependent protein kinase (protein kinase A [PKA]) and subsequent protein phosphorylation. Fig. 3. A signal transductory cascade in the prothoracic glands of M. sexta is elicited by PTTH and results in enhanced synthesis and secretion of ecdysteroid, namely, 3-dehydroecdysone. ER = Endoplasmic reticulum; IP 3 = inositol triphosphate; PLCβ = phospho- lipase Cβ; PIP2 = phosphatidylinositol-4,5-bisphosphate; DAG = diacylglycerol; PKC = protein kinase C; ATP = adenosine triphosphate. (Graphics by R. Rybczynski reproduced with permission.) 132 Part III / Insects / Plants / Comparative PTTH-stimulated PKA activity appears to be necessary for PTTH-stimulated ecdysteroidogenesis, because such ecdysteroid synthesis by prothoracic glands challenged with a PKA-inhibiting cAMP analog is sub- stantially inhibited. Several PTTH-dependent protein phosphorylations have been described for Manduca prothoracic glands including a mitogen-activated protein kinase (MAPK), such as extracellular-regulated kinase (ERK), as well as S6 kinase, the most striking and consistent of these phosphoproteins being the ribosomal protein S6, the phosphorylation of which has been correlated with increased translation of specific mRNAs in several mammalian cell types. In Manduca, rapamycin inhibits both PTTH-stimulated S6 phosphorylation and ecdysteroidogenesis, suggesting that S6 is an integral player in the PTTH transductory cascade. Consistent with this view are the observations that PTTH-stimulated S6 phosphorylation can be readily detected before the PTTH-stimulated increase in ecdysteroid synthesis occurs and that S6 is phosphorylated multiple times in a dose- and time-dependent manner. Over the last several years, a number of studies have revealed that PTTH preparations or cAMP analogs stimulate general protein synthesis in the Manduca prothoracic gland via a branch of the transductory cascade that is distinct from that leading to the activation of ecdysteroidogenesis. PTTH may, therefore, modulate or control the growth status of the prothoracic gland, perhaps independently of its ability to elicit ecdysteroidogenesis, and could play a role in regulating the levels of ecdysteroidogenic enzymes, analogous to pep- tide regulation of enzymes responsible for vertebrate steroid hormone synthesis. Additional factors, such as JH, could determine whether PTTH stimulates or inhibits gland growth, ecdysteroid synthesis, or both. Protein synthesis is required for ACTH stimulation of steroidogenesis in the adrenal cortex as well as for the Manduca prothoracic gland response to PTTH. It is therefore likely that in both the adrenal cortex and prothoracic glands, the phosphorylation state of ribosomal S6 is critical to the relationship between protein synthesis and steroidogenesis. Presumably, the PKA- promoted multiple phosphorylation of ribosomal S6 imparts information to the translational machinery to synthesize specific proteins, which, in turn, regulate some rate-limiting step in ecdysteroid biosynthesis. An interesting outcome of this work is the close analogy observed between control of the insect and mammalian steroidogenic systems. It is obviously a “successful” system in an evolutionary sense, since insects appeared on Earth several hundred million years before mam- mals, and the ancestors of both groups diverged at least 100 million yr before that. Although it is interesting that such divergent groups of animals use the same types of molecules as hormones (peptides, steroids), it is extraor- dinary that they regulate the synthesis of their steroid hormones in an almost identical manner. 3. ECDYSTEROIDS 3.1. Structure-Activity Relationships That ecdysteroids, particularly 20E, elicit the molt is no longer in question and has been established as a cen- tral dogma of the field. What may not be so obvious is that in contrast to vertebrate systems, almost the entire insect is the target of ecdysteroids, e.g., regulation of the growth of motor neurons, control of choriogenesis, stimulation of the growth and development of imaginal disks, initiation of the breakdown of larval structures during metamorphosis, and induction of the deposition of cuticle by the epidermis. Just recently microarray and computational analyses demonstrated that the 20E regulatory network reaches far beyond the molting process in Drosophila melanogaster. The data are based on mutations of the 20E (EcR) receptor and indicate that in the metamorphosis of the midgut, genes that encode a variety of factors are activated by this network and that genes involved in cell cycling are also dependent on 20E for their activation. It is fitting that recent breakthroughs on the mecha- nism of action of ecdysteroids (see Section 3.3.) were accomplished using Drosophila, because it was a bio- assay developed with another fly that was so well uti- lized for the initial crystallization of E and then 20E four decades ago. Since that time, a host of ecdysteroids (Fig. 2B), their precursors, and their metabolites have been identified. We know that the cis-A-B ring junction is essential for molting hormone activity regardless of whether a hydrogen atom or a hydroxyl group is the 5β substituent, as is the 6-oxo-7-ene system in the B ring. The 3β- and 14α-hydroxyl groups are required for high activity in vivo, whereas the presence or absence of hydroxyls at C-2, C-5, or C-11 does not appear to affect biologic activity. The only essential feature of the side chair appears to be the 22β F -hydroxyl. Although E was the first of the ecdysteroids to be crystallized and characterized and thought to be the insect molting hormone 40 yr ago, it is actually converted into the principal molting hormone, 20E, by tissues peripheral to the prothoracic glands (Fig. 1), a reaction mediated by an E 20-monooxygenase. In some insects, particularly the Lepidoptera, as exemplified by Manduca, the major if not sole ecdysteroid synthe- sized and secreted by the prothoracic glands is 3dE (Fig. 2B), which is converted into E by a ketoreductase [...]... between 7dC and 3dE, such as 5α-sterol intermediates, 3-oxo- 4 intermediates, and ∆ 7-5 -6 α-epoxide intermediates, but their intermediacy remains conjectural By contrast, more is known about the terminal hydroxylations necessary for the synthesis of the polyhydroxylated ecdysteroids The enzymes responsible for mediating the hydroxylations at C-2, C-22, and C-25 appear to be classic cytochrome P -4 5 0 enzymes,... inhibitors block PIN1 cycling and and vesicle trafficking Nature 2001 ;41 3 :42 5 42 8 Gomi K, Matsuoka M Gibberellin signalling pathway Curr Opin Plant Biol 2003;6 :48 9 49 3 Gomi K, Matsuoka M Gibberellin signalling pathway Curr Opin Plant Biol 2003;6 :48 9 49 3 Gray WM, Kepinski S, Rouse D, Leyser O, Estelle M Auxin regulates SCFTIR1-dependent degradation of AUX/IAA proteins Nature 2001 ;41 4:271–276 Grazzini E, Guillon... JM, Barbier-Brygoo H, Labiau S, Perrot-Rechenmann C A novel immunological approach establishes that the auxin-binding protein, Nt-abp1, is an element involved in auxin signaling at the plasma membrane J Biol Chem 1999b;2 74: 28,3 14 28,320 Leblanc N, Perrot-Rechenmann C, Barbier-Brygoo H The auxinbinding protein Nt-ERabp1 alone activates an auxin-like transduction pathway FEBS Lett 1999a ;44 9:57–60 Li... in auxin-responsive transcription Plant Cell 2003;15: 533– 543 147 Thornton TM, Swain SM, Olszewski NE Gibberellin signal transduction presents the SPY who O- GlcNAc’d me Trends Plant Sci 1996 ;4: 4 24 42 8 Tyagi AK, Gaur T Light regulation of nuclear photosynthetic genes in higher plants Crit Rev Plant Sci 2003;22 :41 7 45 2 Ueguchi C, Sato S, Kato T, Tabata S The AHK4 gene involved in the cytokinin-signaling... decline steadily In rats and pigs, serum concentrations of IGF-2 are greater at birth and decrease with age In the bovine, IGF-1 and -2 are not only detectable in serum but also in colostrum and milk Plasma concentrations of IGF-1 in cattle are dependent on nutritional status through both GH-dependent and -independent mechanisms In mature cattle, the ability of GH to maintain plasma IGF-1 is impaired when... preoptic area (SDN-POA) has been identified in rats This SDN-POA has been found to be correlated with male copulatory patterns and sexual partner preference In male rats treated perinatally with the aromatase inhibitor 1 ,4, 6-androstatriene-3,17-dione, the volume of SDN was positively correlated with maletypical sexual behavior and female-directed partner preference In humans, the third interstitial nucleus... mitochondrial and the latter microsomal The sequence of hydroxylation is C-25, C-22, and C-2 Very recently, studies on a series of Drosophila embryonic lethal mutations have allowed the cloning and characterization of those genes encoding the P -4 5 0 enzymes responsible for the terminal hydroxylations leading to the production of E and the monooxygenase that mediates the conversion of E into 20E (Gilbert, 20 04) ... 133 analysis, all four genes that encode P -4 5 0 enzymes that mediate the last four hydroxylations in 20E biosynthesis have been identified and characterized (see the structure of cholesterol and 20E in Fig 2B; hydroxylations at C-2, C-20, C-22, and C-25) Once formed, 3dE is converted into E through the mediation of a hemolymph ketoreductase in the Lepidoptera, and the E is then transformed into 20E at... Lopez-Molina L, Himmelbach A, Grill E, Chua NH The abi 1-1 mutation blocks ABA signaling downstream of cADPR action Plant J 2003; 34: 307–315 Chapter 11 / Comparative Endocrinology 149 11 Comparative Endocrinology Fredrick Stormshak, PhD CONTENTS INTRODUCTION ENDOCRINE CONTRIBUTIONS TO BEHAVIOR STRESS AND THE AMPLECTIC CLASP ENDOCRINE BASIS OF MALE-ORIENTED SEXUAL BEHAVIOR GROWTH AND DEVELOPMENT PUBERTY ENDOCRINOLOGY. .. Biochem 1996; 34: 133–138 Finkelstein RR, Gampala SSL, Rock CD Abscisic acid signaling in seeds and seedlings Plant Cell 2002; 14: 15 45 Friml J, Benkova E, Ikram, Blilou I,Wisniewska J, Hamann T, Ljung K, Wood S, Sandberg G, Scheres B, Palme K AtPIN4 mediates 146 sink-driven gradients and root patterning in Arabidopsis Cell 2002b;108:661–673 Friml J, Palme K Polar auxin transport—old questions and new concepts? . 5β substituent, as is the 6-oxo-7-ene system in the B ring. The 3 - and 14 -hydroxyl groups are required for high activity in vivo, whereas the presence or absence of hydroxyls at C-2, C-5, or C-11 does not. the target glands (i.e., the prothoracic glands). Correlations have been reported between PTTH levels in the hemolymph and the molting hormone titer for both Manduca and Bombyx and, in both. stereospecific removal of the 7β-hydrogen to form 7-dehydrocholesterol (7dC), a sterol rel- egated to the prothoracic glands of Manduca and other Lepidoptera. This cholesterol 7,8-desaturating activity in

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