My road to Damascus: how I converted to the prohormone theory and the proprotein convertases.

My desire as a young endocrinologist to improve my clinical skills through a better knowledge of hormone chemistry led me to serendipitous discoveries and unexpected horizons. The first discovery, published in 1967, revealed that peptide hormones are derived from endoproteolytic cleavages of larger precursor polypeptides. It was the foundation of the prohormone theory. Initially thought to apply to a few hormones, the theory rapidly extended to many proteins, including neuropeptides, neurotrophins, growth and transcription factors, receptors, extracellular matrix proteins, bacterial toxins, and viral glycoproteins. Its endoproteolytic activation mechanism has become a fundamental cellular process, affecting many biological functions. It implied the existence of specific endoproteolytic enzymes. These proprotein convertases were discovered in 1990. They have been shown to play a wide range of important roles in health and disease. They have opened up novel therapeutic avenues. Inactivation of PCSK9 to reduce plasma cholesterol is currently the most promising. To make this good thing even better, I recently discovered in a French Canadian family a potent PCSK9 (Gln152His) mutation that significantly lowers plasma cholesterol and should confer cardiovascular longevity. The discovery helped me to complete the loop: "From the bedside to the bench and back to the bedside."

Ghrelin: more than a new frontier in neuroendocrinology.

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as natural ligand of the growth hormone secretagogue receptor (GHS-R) type 1a. More recently, ghrelin attracted enormous interest as new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also non-endocrine actions (e.g. cardiovascular activities) that are explained by the widespread distribution of ghrelin and GHS-R expression. The existence of GHS-R subtypes and evidence that neuroendocrine but not all other ghrelin actions are dependent on acylation in serine 3 add further complexity to the system whose major physiological role remains to be definitely clarified. What we are learning from the studies about the control of ghrelin secretion is that it is mostly under metabolic control; the most important impact of ghrelin would, in turn, be metabolic. However, a recent study states that the ghrelin knockout (KO) mouse is not anorectic dwarf and this evidence clearly depicts a remarkable difference from the leptin KO mouse. Nevertheless, the original and fascinating ghrelin story as well as its potential pathophysiological implications in endocrinology and internal medicine are not definitely canceled by this evidence. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, open questions that are waiting for an answer are: how many are the ghrelin receptors? Is ghrelin the or a GHS ligand, i.e. are there other natural GHS-R ligands? Is there a functional balance between acylated and unacylated ghrelin forms that would play different actions? Within the next years these questions will find the appropriate answer and we'll know about the ghrelin system something more precise; this knowledge will more appropriately clarify the potential clinical perspectives.

A centenary of gastrointestinal endocrinology.

Gastrointestinal hormones are peptides released to circulation from endocrine cells as well as neurons in the gastrointestinal tract. More than 30 hormone genes are currently known to be expressed in the stomach and intestines, which makes the gut the largest endocrine organ in the body. Moreover, cell and molecular biology now makes it feasible to conceive gastrointestinal endocrinology under five general headings: 1) The structural homology groups the hormones into eight families, each of which is assumed to originate from a common ancestral gene; 2) the individual hormone gene often have multiple phenotypes due to alternative splicing of the primary transcript, tandem organization of the translational product or differentiated maturation of the prohormone. By a combination of these mechanisms, more than 100 different hormonally active peptides are released from the gastrointestinal tract; 3) in addition, gut hormone genes are also widely expressed outside the gut, some only in neurons and/or in endocrine cells, but others also in other extraintestinal cell-types; 4) the different cell types may express different hormonally active fragments of the same prohormone by variation in the cell-specific posttranslational processing. Finally, 5) endocrine cells, neurons, and spermatozoa display different cell-specific release of gut peptides, so the same peptide may act as a metabolic blood-borne hormone, as a neurotransmitter, as a long-acting growth factor, and as an acute fertility factor.

Ghrelin for the gastroenterologist: history and potential.

Ghrelin, a novel 28-amino acid orexigenic peptide discovered in 1999, has given us further insights into the control of energy homeostasis and growth hormone secretion. As a natural endogenous ligand of the growth hormone secretagogue receptor, it potently stimulates growth hormone release but is also implicated in many other homeostatic mechanisms. Released from the stomach, it stimulates lactotroph and corticotroph secretion, increases appetite and adiposity, has beneficial hemodynamic effects, has prokinetic and gastric acid secretory functions in the stomach, and may even be implicated in sleep. As advances in the understanding of appetite and obesity are made, it is timely to review the possibly central role of ghrelin in these physiological and pathophysiological states. This review will discuss the recent literature concerning this exciting novel neuropeptide and discuss the possible therapeutic possibilities it may open up to us.