Regulatory peptides and systems biology: A new era of translational and reverse‐translational neuroendocrinology

Abstract

Recently, there has been a resurgence in regulatory peptide science as a result of three converging trends. The first is the increasing population of the drug pipeline with peptide-based therapeutics, mainly in, but not restricted to, incretin-like molecules for treatment of metabolic disorders such as diabetes. The second is the development of genetic and optogenetic tools enabling new insights into how peptides actually function within brain and peripheral circuits to accomplish homeostatic and allostatic regulation. The third is the explosion in defined structures of the G-protein coupled receptors to which most regulatory peptides bind and exert their actions.These trends have closely wedded basic systems biology to drug discovery and development, creating a "two-way street" on which translational advances travel from basic research to the clinic, and, equally importantly, "reverse-translational" information is gathered, about the molecular, cellular and circuit-level mechanisms of action of regulatory peptides, comprising information required for the fine-tuning of drug development through testing in animal models. This review focuses on a small group of 'influential' peptides, including oxytocin, vasopressin, pituitary adenylate cyclase-activating polypeptide, ghrelin, relaxin-3 and glucagon-like peptide-1, and how basic discoveries and their application to therapeutics have intertwined over the past decade. K E Y W O R D S neuroendocrinology, regulatory peptide, therapeutics, translation How to cite this article: Eiden LE, Gundlach AL, Grinevich V, et al. Regulatory peptides and systems biology: A new era of translational and reverse-translational neuroendocrinology.

Analgesic effect of central relaxin receptor activation on persistent inflammatory pain in mice: behavioral and neurochemical data

“…24 Neuronal plasticity is also shaped by regulatory molecules, among which neuropeptides act by binding to G-protein-coupled receptors. Various neuropeptide and receptor systems are highly versatile in function and play key roles in pathophysiological conditions, 21,32 especially chronic pain. 22,75 How neuropeptides control pain largely depends on their site of release and target cells.…”

Role of Oxytocin and Vasopressin in Neuropsychiatric Disorders: Therapeutic Potential of Agonists and Antagonists

“…Perhaps due to the limited number of molecules that act on OT and/or AVP receptors, there are virtually no examples of promiscuous drugs with described effects on these GPCRs. Far from considering this scenario as a limitation, we see it as a great opportunity to enter a highly unexplored field of research with significant potential for the development of new CNS polypharmaceuticals [ 218 , 219 , 220 ]. Therefore, for instance, it is important to mention that balovaptan and nelivaptan have a greatly similar profile, antagonizing the three proteins, OT-R, V 1A R, and V 1B R, although with differential potency.…”

Neurolysin substrates bradykinin, neurotensin and substance P enhance brain microvascular permeability in a human in vitro model

“…[2][3][4][5] The contribution of neurone-derived signalling molecules on the maintenance and disruption of the BBB during ischaemic stroke remains the focus of ongoing studies. In particular, the contribution of neuropeptides, which represent the largest group of signalling molecules with pleiotropic functions, 6 remains understudied. The possible contribution of neuropeptides in the response of BBB to ischaemic injury is of critical importance because neuropeptides are commonly considered as the 'language of the stressed nervous system', and their expression is especially increased following various stressors.…”

“…Nln (neurolysin; EC3.4.24.16) is a zinc metallopeptidase containing a His-Glu-X-X-His domain, which is maximally active at neutral pH and is widely distributed in both central and peripheral nervous system 14,15. Nln functions to regulate the levels of several extracellular neuropeptides, including neurotensin, bradykinin, substance P, angiotensin I and II, metamorphamide, dynorphin A(1)(2)(3)(4)(5)(6)(7)(8) and haemopressin 17,67,68. These substrate peptides are hydrolysed and inactivated by Nln, except angiotensin I, metamorphamide and dynorphin A (1-8), which are hydrolysed and converted into angiotensin-(1-7), Met-and Leu-enkephalins, respectively 20.…”