The Melanotropic Peptides

Volume I: Source, Synthesis, Chemistry, Secretion, Circulation and Metabolism

M.E. Hadley

• Publisher: CRC Press
• Year: 2018
• Print ISBN: 9781315895291
• eBook ISBN: 9781351091299
• Topic: Medicine
• Subtopic: Alternative & Complementary Medicine

The three volumes on "The Melanotropic Peptides" are the outcome of a conference of the same name that was held in Tucson, Arizona, from October 11-12, 1986. The format of the three volumes provides a complete coverage of what is known about the Melanotropic Peptides. Volume I provides information on the source, synthesis, chemistry, mechanism of secretion, control of secretion, and the circulation and metabolism of the melanotropic peptides.

Chapter 1
THE MELANOTROPIC PEPTIDES: AN INTRODUCTION

Philip J. Lowry

It was early in this century that the involvement of the pituitary gland in the control of color change was first recognized. Naturally, experiments were performed on amphibia since by simple observation they could be seen to change their pigmentation in adapting to background color. By surgical removal of the pituitary rudiments it could be shown that larval amphibians developed into pale individuals,^1,2 and that either implanting pituitaries into pale tadpoles or using pituitary extracts it was concluded that a humoral factor was responsible in causing the dispersion of melanin in the melanophores of the skin, this movement of pigment being seen as an overall darkening. Thereafter, it was generally agreed that where an anatomically distinct pars intermedia existed then it was there that most of the melanotropic bioactivity resided.

Although it was the amphibians which provided the means of measuring melanotropic activity, it was the domestic mammals which were to provide a rich source of the material responsible for their final characterization. To add to the then already confused state of the knowledge of the endocrinology of these hormones in mammals, during the 1950s, two distinct peptides were purified and characterized and thus termed α- and β-MSH.

After sequence analysis, both peptides were found to be related structurally, possessing the common heptapeptide core sequence Met-Glu-His-Phe-Arg-Trp-Gly which was shown to possess inherent melanotropic activity (for review see Reference 3). Since it was recognized that α-MSH had the same amino-acid sequence as the N-terminal portion of corticotropin and the β-MSH sequence occupied the mid-portion of β-lipotropin (β-LPH), it seemed natural to postulate that these larger peptides acted as precursors for the smaller melanotropins. The discovery of the C-terminal fragment of ACTH (CLIP) and its occurrence in the intermediate lobe⁴ and later on the C-terminal fragment from β-LPH the opiate peptide β- endorphin provided further evidence for this hypothesis. Since the melanotropic activity had been observed in early studies to reside mainly in the intermediate lobe, it was proposed that ACTH and β-LPH were synthesized in both the corticotrophs of the pars distalis and all the cells of the pars intermedia. In the former, the parent peptides were secreted intact, whereas in the pars intermedia they were fragmented by specific enzymic mechanisms and modified (e.g., acelytation) to form the smaller fragments, particularly the melanotropins.⁵ One peptide which did not fit into this pattern was human β-MSH, but this was later found to be an extraction artifact rather than a true processed peptide.⁶

It was the elegant work of Mains and Eipper (for review see Reference 7) who originally used the rat ATt20 pituitary tumor-cell line and later extended their studies to the pars intermedia, who, by using a variety of antisera and pulse-chase experiments, demonstrated the existence of a large precursor for ACTH and LPH of a molecular weight of some 30,000 daltons. A similar conclusion was reached by Roberts and Herbert⁸ who immunologically characterized the translated product in vitro of m-RNA isolated from the neurointermediate lobe.

The cloning and sequencing of the c-DNA encoding the whole of the ACTH/LPH precursor, finally resolved this fascinating phenomenon.⁹ More importantly, they had used as their starting material mRNA isolated from the pars intermedia not normally thought of as a source of ACTH and β-LPH. They demonstrated, however, from this pars-intermedia-derived material that ACTH occupied the mid-portion and β-LPH the C-terminal of a large precursor. These peptides were separated from each other by pairs of basic amino acids and from a large N-terminal peptide which contained a third melanotropic sequence (γ-MSH).

This γ-MSH precursor had been identified earlier by Mains and Eipper⁷ to be glycosylated and had been termed the 16K fragment, although they did not realize at that time that it contained a melanotropic sequence. Thus, it would appear that three melanotropic sequences occur within the intermediate lobe (and pars distalis) precursor for these peptides. While the cloning of this precursor has vastly increased our knowledge of the way in which these peptides are biosynthesized, it has done litle to help in our understanding of their biological significance. The situation in the lower vertebrates is not so much a problem since here it can be clearly demonstrated that they do at least change color and do respond to physiological changes in blood melanotropin levels by changing color. In mammals, the situation is difficult to fully understand. First of all, there are a number of mammals which have little or no intermedia tissue at all, this includes: man, the higher apes, elephants, manatees, whales, dolphins, and the armadillo. When attempts have been made, little evidence has been found for the existence of melanotropins being manufactured in the pars distalis corticotrophs and certainly in man, the only time when α-MSH can be identified has been in the fetal pituitary where a band of cells resembling intermedia tissue can be observed. Even then, the peptide was found to be lacking N-terminal acetylation,¹⁰ and a peptide resembling β-MSH has never been identified.¹¹ If the pars intermedia in the other mammals where the melanotropins are found displayed little biosynthetic activity, then one could assign the tissue to join the ranks of the vestigial organs. Unfortunately, intense biosynthetic activity can be seen, particularly if the dopaminergic tonic inhibition is removed either surgically or pharmacologically. Despite the hypersecretion of several other peptides along with the melanotropins under these conditions, most scientists agree that in mammals at least, it is extremely difficult to see any physiological change in the animals. At the 1987 Ciba Foundation Symposium, we suggested that species with a highly evolved brain, indeed, the species listed above represent some of the most intelligent in the animal kingdom, have lost the need for a pars intermedia in adult life and lent credence for a role for the pars intermedia peptides in learning and behavior.¹¹ Despite the ensuing 5 years of intense scientific activity, little evidence has come to light of a convincing function for the pars intermedia and the melanotropins in mammals. The problem is compounded by the fact that when a weak, but unique biological action can be assigned to for example α-MSH, because at least six other peptides with other unique biological actions are co-secreted with it, the physiological consequences are difficult to explain. Even in the lower vertebrates, the co-secretion of three melanotropins in an animal such as the dogfish appears a little paradoxical. Immunoneutralizing α-MSH with an antiserum which only recognizes the heptapeptide core of α-MSH caused dark animals to pallor.¹² The antiserum, because of its specificity, however, would not be expected to immunoneutralize γ-MSH and β-MSH where the core sequence is changed despite their melanotropic activity. What other biological actions the other POMC peptides are expressing in these animals is a matter for further research.

Let us hope that at the culmination of this meeting on melanotropins held in Tucson, Arizona, new aspects of this tantalizing subject will come to light and we will be able to at last assign a function to the mammalian pars intermedia and the peptides it elaborates, especially the melanotropins.

References

1. Smith, D. C., The effect of hypophysectomy in the early embryo upon the growth and development of the frog, Anat. Rec., 11, 57, 1916.

2. Atwell, W. J., On the nature of the pigmentation changes following hypophysectomy in the frog larva, Science, 49, 48, 1919

3. Hofman, K., Chemistry and function in polypeptide hormones, Ann. Rev Biochem , 31, 213, 1962

4. Scott, A. P., Ratcliffe, J. G., Recs, L. H., Landon, J., Bennett, H. P. J., Lowry, P. J., and McMartin, C., A new pituitary peptide. Nature, (London) New Biol., 224, 65, 1973

5. Lowry, P. J. and Scott, A. P., The evolution of ACTH and MSH, Gen. Comp. Endocrinol , 26, 16, 1975.

6. Bloomfield, G. A., Scott, A. P., Silkes, J. J. H., Lowry, P. J., and Rees, L. H., Human beta-MSH, a reappraisal. Nature, 252, 492, 1974.

7. Mains, R. E. and Eipper, B. A., Biosynthetic studies on ACTH, β-endorphin and α-melanotropin in the rat, Ann. N.Y. Acad. Sci., 343, 94, 1980.

8. Roberts, J. L. and Herbert, E., Characterization of a common precursor to corticotropin and β-lipotropin, Identification of β-lipotropin peptides and their arrangement relative to corticotropin in the precursor synthesized in a cell free system, Proc. Natl. Acad Sci U.S.A. 74, 5300, 1977.

9. Nakanishi, S., Inoue, A., Kita, T., Nakamura, M., Chang, A. C. Y., Cohen, S. N., and Numa, S., Nucleotide sequence of cloned c-DNA for bovine corticotropin-β-hpotropin precursor. Nature, 278, 423, 1978

10. Tilders, F. J. H., Parker, C. R., Barnea, A. and Porter, J. C., The major immunoreactive melanocyte stimulating hormone (γ-MSH)-like substance found in human fetal pituitary is not α-MSH but may be desacetyl α-MSH (adrenocorticotropin 1-13-NH,), J Clin. Endocrinol., Metab., 52, 319, 1981.

11. Jackson, S., Hope, J., Estivariz, F. E., and Lowry, P. J., Nature and control of peptide release from the pars intermedia, in Peptides of the Pars Intermedia, Ciba Foundation Symposium 81, Evered, D. and Lawrenson, G., Eds., Pitman Medical, London, 1981, 141

12. Sumpter, J. P., Denning-Kendall, P. A., and Lowry, P. J., The involvement of melanotropins in physiological colour change in the dogfish, Scyhorhinus canicula, Gen Comp. Endocrinol., 56, 360, 1984.

Chapter 2
MELANOTROPINS: PARS INTERMEDIA STRUCTURE AND FUNCTION

Elizabeth K. Perryman

• I. Introduction
• II. Morphology of the Pars Intermedia
  • A. Overview of Development
  • B. Comparative Aspects of Gross Anatomy
  • C. Vascular Supply
• III. Granular Cells
  • A. Cytology
  • B. Innervation
• IV. Nongranular Cells
  • A. Cytology
    • 1. Folliculo-Stellate System
    • 2. Follicle and Cleft
  • B. Suggested Roles for Nongranular Cells
  • C. Extracellular Channel System
• V. Concluding Remarks
• Acknowledgements
• References

I. Introduction

While this review of the structure of the pars intermedia (PI) and the morphological aspects of secretion will emphasize the recent scientific advances, it is important to consider the past literature which has led to these discoveries. Thus, an effort will be made to relate the data of the last 10 years to important concepts already established by the more classical anatomical techniques. Also, at times, a comparison of the PI of various vertebrates will be used in order to provide a more comprehensive picture. Because of the present limitation of space and previously published volumes, it is suggested that the reader be aware of the following publications. An excellent comprehensive volume with a comparative approach is The Pituitary Gland¹ published in 1974. More recent data of the 1980s are included in a review of the PI by Weatherhead,² relating structure with function, and also the book, Ultrastructure of Endocrine Cells and Tissues,³ which contains chapters on fine structure of various portions of the pituitary gland. Within the present review, the morphology of the components (e.g., cell types, follicles, vascularity) will be related to melanotropin secretion.

II. Morphology of the Pars Intermedia

A. Overview of Development

The pituitary gland has two embryonic origins. The neurohypophysis differentiates from the neural ectoderm of the infundibular floor of the third ventricle of the brain; the adenohypophysis forms from Rathke’s pouch, an oral ectodermal invagination from the stomodeum. The neurohypophysis in tetrapods and lungfish is divided into two neurohemal areas, an anterior median eminence and a posterior neural lobe or pars nervosa (PN). The form and degree of anatomical association of the neurohypophysis with the adenohypophysis vary in the different vertebrate classes. Evidently, the neural ectoderm induces the formation of the pars intermedia (PI) where this ectoderm makes contact with the hindmost part of Rathke’s pouch. No PI forms in vertebrates, such as birds, in...

Table of contents

• Cover
• Title Page
• Copyright Page
• Preface
• The Editor
• Contributors
• Table of Contents
• Chapter 1 The Melanotropic Peptides: An Introduction
• Chapter 2 Melanotropins: Pars Intermedia Structure and Function
• Chapter 3 Pituitary Melanotropin Biosynthesis
• Chapter 4 The Melanotropic Peptides: Structure and Chemistry
• Chapter 5 Melanocyte-Stimulating Hormone in the Central Nervous System
• Chapter 6 The Pro-Opiomelanocortin Gene In Xenopus Laevis: Structure, Expression, And Evolutionary Aspects
• Chapter 7 Regulation Of Pro-Opiomelanocortin (Pomc) Biosynthesis In The Amphibian And Mouse Pituitary Intermediate Lobe
• Chapter 8 Pro-Opiomelanocortin In The Amphibian Pars Intermedia: A Neuroendocrine Model System
• Chapter 9 Multihormonal Control Of Melanotropin Secretion In Cold-Blooded Vertebrates
• Chapter 10 Melanotropin Enzymology
• Chapter 11 Peripheral and Central Pharmacokinetics of the Melanotropins
• Index