Molecular Biology of Serotonin Receptors - Structure and Function at the Molecular Level

Abstract

Front cover (paperback): South wall of a mural depicting Detroit Industry, 1932-33 (fresco), Rivera, Diego (1886-1957)/Detroit Institute of Arts, USA/Gift of Edsel B. Ford/Bridgeman Images. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cold Spring Harbor xiv Foreword The year 2015 marked the sesquicentennial anniversary of Gregor Mendel's landmark 1865 presentation of his paper "Experiments on Plant Hybridization," which laid the groundwork for modern genetics. Seminal discoveries throughout the 20th century followed, not least of which was the demonstration that chromatin carried traits, the formalization of the concept of the gene as the hereditary unit, the discovery of DNA as the hereditary material, the discovery of the double helix structure of DNA, and the elucidation of many mechanisms now known to operate to express and protect the hereditary material in its nuclear, cellular, and organismal context. The year also marked the 125th anniversary of Cold Spring Harbor Laboratory as well as the 80th Cold Spring Harbor Laboratory Symposium on Quantitative Biology, the preeminent and storied series of landmark meetings initiated by Reginald Harris in 1933. It therefore seemed fitting to focus this year's Symposium on 21st Century Genetics: Genes at Work to provide a current synthesis of genetic mechanisms and genome/chromosome biology. The decision to plan the 2015 Symposium on this theme reflects the enormous research progress achieved in recent years, and it was intended to provide a broad synthesis of the current state of the field, setting the stage for future discoveries and application. Opening night speakers included Robert Tjian (HHMI and UC Berkeley) on probing transcription regulation by single-molecule imaging; Denis Duboule (EPF Lausanne, Switzerland), who spoke about long-range regulation during development and evolution; Ron Evans (Salk Institute for Biological Studies) on nuclear receptors-feast, famine, and physiology; and Angelika Amon (Massachusetts Institute of Technology), who addressed the effects of aneuploidy on cellular fitness and tumorigenesis. Svante Pääbo (Max Planck Institute for Evolutionary Anthropology, Germany) addressed The Genetic Legacy of Neanderthals in an outstanding Dorcas Cummings Lecture for Laboratory friends, neighbors, and Symposium participants in advance of the annual dinner parties. Susan Gasser provided a masterful Summary at the conclusion of the Symposium immediately before the final banquet. This Symposium was attended by almost 350 scientists from universities around the country and the world, and the program included 65 invited presentations and 135 poster presentations. To disseminate the latest results and discussion of the Symposium to a wider audience, attendees were able to share many of the Symposium talks with their colleagues who were unable to attend using the Leading Strand video archive.

Are Caenorhabditis elegans receptors useful targets for drug discovery: Pharmacological comparison of tyramine receptors with high identity from C. elegans (TYRA-2) and Brugia malayi (Bm4)

“…In contrast, all Gα i/o characterized receptors fall into clade II and we predict that AsTA/OA, CbP1888, AgTA2, PxTA, BmiOA, LsOA2, Bm4, CbP02670 are Gα i/ocoupled TA receptors. Based on an analysis of the sequence alignments, 41 aa are conserved in the TA/OA GPCR family; this number is significantly higher than the 33 aas that are conserved in the 12 human 5-HT receptors reported previously [45]. Interestingly, 65 aas that are conserved in both TYRA-2 and Bm4 are different in other Gα i/o clustered receptors, supporting the pharmacological differences between TYRA-2 and SER-2 reported previously [6,9].…”

Activation of 5-HT6 Receptors Modulates Sleep–Wake Activity and Hippocampal Theta Oscillation

“…46−48 However, increase or decrease in the serotonin level by reuptake inhibitors or blockade of 5-HT synthesis, respectively, do not have such global effects on the occurrence of theta rhythm, 49,50 suggesting a more delicate serotonergic involvement in the regulation of forebrain oscillations. The complexity of this regulation is supported by a significant diversity of 5-HT neurons 51−54 and by the wide variety of 5-HT receptors 55 their diverse anatomical distribution, and neuronal expression which may induce nonuniform serotonergic actions at different targets and during different behaviors.…”

Cocaine-mediated supersensitivity of 5-HT2A receptors in hypothalamic paraventricular nucleus is a withdrawal-induced phenomenon

“…Although, the mechanisms by which cocaine withdrawal mediates 5-HT 2A receptor supersensitivity in PVN are not completely understood, our present and published data indicates that they could involve: (1) increased density of 5-HT 2A receptors in a âhigh-affinityâ state at least at 24 h of withdrawal; and (2) increased levels of membrane-associated GÎ q and GÎ 11 proteins at 48 h of withdrawal. As 5-HT 2A receptors in PVN are important for the regulation of mood, impulse control and responses to stressors (Kroeze et al, 2002;Aghajanian and Marek, 2000), withdrawal-induced increases in 5-HT 2A receptor function in this limbic region may be clinically relevant with respect to drug relapse. Time-dependent supersensitivity of the (â)DOI-induced neuroendocrine responses in cocainetreated rats at various post-treatment withdrawal times.…”

“…GÎ q and GÎ 11 proteins were examined because these are the G-proteins that mediate 5-HT 2A receptor function. As 5-HT 2A receptors in PVN are important for the regulation of mood, impulse control and responses to stressors (Kroeze et al, 2002;Aghajanian and Marek, 2000), withdrawal-induced increases in 5-HT 2A receptor function in this limbic region may be clinically relevant with respect to drug relapse.…”