The Cell Biology Neuropeptide Hormones

To understand peptide hormone biosynthesis and their action at a distant target cell, we need first to comprehend the cell biology of these molecules, their origin, and the mechanism by which they became biologically active. Today we know that all peptide hormones and many nonhormonal proteins derived from larger inactive precursor proteins, which are posttranslationally modified to produce an array of different peptides with specific biological function and secretion patterns. The biosynthesis of neuropeptide hormones from their larger inactive precursor proteins and their traffic to the regulated secretory pathway (RSP) for cellular release is one of the paramount cellular processes in hormone action. In early times of peptide discovery, the “peptidergic neuron” name was reserved for those neurosecretory cells within the hypothalamus that released oxytocin and vasopressin directly into the circulation from their nerve terminals in the posterior pituitary. The idea of neurosecretion in the hypothalamus can be traced back to the work of Scharrer and Scharrer (Scharrer and Scharrer 1940) as early as the late 1920s. Later work by Harris and colleagues specified that the hypothalamic substances secreted into the portal vessels were pituitary specific and led to the concept of “releasing factors” whose purpose was to initiate a cascade of events resulting in the release of peripherally active hormones (Fink 1976). The discovery and chemical characterization of the first identified hypothalamic releasing factor, thyrotropin-releasing hormone (pyroGlu-His-ProNH2, also known as thyroliberin, and herein referred to as TRH), by Guillemin and colleagues (Burgus et al. 1969) and Schally and colleagues (Boler et al. 1969) provided ultimate confirmation for the founding principles of neuroendocrinology which resulted later in the discovery of other releasing factor peptides (Guillemin 1978; Schally 1978). Recent progress over the last decades in genetics and molecular biology provided considerable information about the expression of brain neuropeptide hormone genes and their tissue-specific regulation. From multiple studies conducted in many laboratories including ours, it has become clear that neuropeptides acting as neurotransmitters or hormones play a significant modulatory roles in the control of the central nervous system and neuroendocrine function. Even more remarkable was the discovery that multiple neuropeptides derived from posttranslational processing of its single gene- polypeptide precursor has distinct physiological functions (Nillni and Sevarino 1999; Eipper and Mains 1980; Nillni et al. 1996; Liston et al. 1984; Hall and Stewart 1983; Nillni 2007, 2010; Wardlaw 2011). Therefore, to fully understand the biology of neuropeptide hormones controlling energy balance, it is essential to uncover the mechanisms by which a specific prohormone is posttranslationally modified to its active form under normal and pathological conditions, a process that happens in a tissue-specific manner. This topic will be discussed in this chapter putting emphasis on three prohormones, pro-thyrotropin-releasing hormone (pro-TRH), pro-opiomelanocortin (POMC), and pro-corticotropin-releasing hormone (pro-CRH).