Molecular Neuroendocrinology

From Genome to Physiology

David Murphy, Harold Gainer

• Publisher: Wiley-Blackwell
• Year: 2015
• ISBN:
  9781118760338
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

Molecular Neuroendocrinology: From Genome to Physiology, provides researchers and students with a critical examination of the steps being taken to decipher genome complexity in the context of the expression, regulation and physiological functions of genes in neuroendocrine systems.

The 19 chapters are divided into four sectors: A) describes and explores the genome, its evolution, expression and the mechanisms that contribute to protein, and hence biological, diversity. B) discusses the mechanisms that enhance peptide and protein diversity beyond what is encoded in the genome through post-translational modification. C) considers the molecular tools that today's neuroendocrinologists can use to study the regulation and function of neuroendocrine genes within the context of the intact organism. D) presents a range of case studies that exemplify the state-of-the-art application of genomic technologies in physiological and behavioural experiments that seek to better understand complex biological processes.

•Written by a team of internationally renowned researchers
•Both print and enhanced e-book versions are available
•Illustrated in full colour throughout

This is the third volume in a new Series 'Masterclass in Neuroendocrinology', a co- publication between Wiley and the INF (International Neuroendocrine Federation) that aims to illustrate highest standards and encourage the use of the latest technologies in basic and clinical research and hopes to provide inspiration for further exploration into the exciting field of neuroendocrinology.

Series Editors: John A. Russell, University of Edinburgh, UK and William E. Armstrong, The University of Tennessee, USA

Part A
Genome and Genome Expression

CHAPTER 1
Evolutionary Aspects of Physiological Function and Molecular Diversity of the Oxytocin/Vasopressin Signaling System

Zita Liutkevičiūtė and Christian W. Gruber

Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

1.1 Evolution of peptidergic signaling

One of the major eukaryotic signal transduction machineries is composed of G protein-coupled receptors (GPCRs) and their associated signaling molecules (see Chapter 10). GPCRs share a seven α-helical transmembrane architecture with an extracellular N-terminus and an intracellular C-terminus, and are able to sense a diverse set of ligand molecules, including proteins, peptides, amino acids, nucleosides, nucleotides, ions, and photons. GPCRs are involved in many processes such as cell growth, migration, density sensing or neurotransmission (Gruber et al., 2010).

Proteins comprising a seven-transmembrane topology have been identified as far back in the evolutionary timeline as prokaryotes; these are, for instance, light-sensitive proteo-, bacterio- and halorhodopsin proteins that are involved in non-photosynthetic energy harvesting in Archaea and bacteria. Structurally similar sensory rhodopsin proteins can also be found in eukaryotes, but to determine the phylogenetic relationship between prokaryotic and eukaryotic GPCRs is rather difficult, since (i) the prokaryotic and eukaryotic proteins have evolved independently for approximately 1.2 billion years, which resulted in low sequence conservation, and (ii) the occurrence of lateral gene transfer between prokaryotes and eukaryotes has been reported for certain microbial rhodopsins, which further complicates the analysis of phylogenic relations (Strotmann et al., 2011).

Recent studies on the evolution of GPCR signaling systems in eukaryotes – covering not only the receptors and their cognate G proteins, but also upstream and downstream regulators of the system – concluded that the last eukaryotic common ancestor must have already expressed a complex repertoire of GPCRs. Furthermore, it has been suggested that different parts of the GPCR signaling system evolved independently, and that some of them have been lost or became simplified without disrupting overall signaling functionality. For instance, most organisms contain most of the known GPCR signaling components, but certain species have retained only a subset of those, whereas others are completely reduced. These findings suggest that the GPCR signaling system is modular and that during evolution, drastic rearrangements can occur without complete loss of functionality. Analyses of protein domain architectures additionally suggest that domain shuffling is a major mechanism of signaling system evolution (de Mendoza et al., 2014).

Gene families and protein domain architectures of cytoplasmic transduction elements (for example, G proteins, arrestins, regulators of G protein signaling, guanine nucleotide exchange factors) are largely conserved between unicellular holozoans and metazoans. In contrast, receptors underwent a dramatic expansion in metazoans compared to their closest unicellular relatives. For instance, the human and mouse genomes code for more than 800 and 1300 GPCRs, respectively, which equals more than 1% of the total predicted genes, while yeast has as little as 10 GPCR genes, less than 0.2% of the total predicted genes (de Mendoza et al., 2014; Fredriksson and Schioth, 2005). This could be due to adaptation of GPCR signaling systems for new functions, such as cell–cell communication, developmental control, and complex environmental sensing, from light to odor and taste (de Mendoza et al., 2014). However, most GPCRs do not play a primary vital role in these organisms. Only 8% of GPCR genes in mice responded to gene disruption by embryonic or perinatal lethality; about 41% exhibited an obvious phenotype and more than 50% of knockout mice of individual GPCRs display no obvious phenotypical change (Schoneberg et al., 2004). However, in humans, mutations in genes encoding GPCRs and G proteins result in pathological conditions, for instance severe vision impairment and blindness, and many other retinal, endocrine, metabolic or developmental disorders (Schoneberg et al., 2004).

1.1.1 Evolution and diversity of peptide G protein-coupled receptors and their endogenous ligands

Of particular interest for this chapter are peptidergic systems, which are generally defined as a functional complex consisting of a cell that synthesizes and releases a peptide mediator, a cell that responds to that peptide by a certain physiological change, and the process of transferring the peptide from the site of synthesis to the site of action. In particular, we use the term peptidergic signaling for pathways that are mediated by peptides, their endogenous re...

Table of contents

• Cover
• Title Page
• Table of Contents
• List of Contributors
• Series Preface
• About the Companion Website
• Introduction
• Part A: Genome and Genome Expression
• Part B: Proteins, Posttranslational Mechanisms, and Receptors
• Part C: The Tool Kit
• Part D: Case Studies – Integration and Translation
• Glossary
• Index
• End User License Agreement