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Reid H.J. Olsen

Bio: Reid H.J. Olsen is an academic researcher from University of North Carolina at Chapel Hill. The author has contributed to research in topics: G protein-coupled receptor & Receptor. The author has an hindex of 22, co-authored 39 publications receiving 1580 citations. Previous affiliations of Reid H.J. Olsen include Oregon Health & Science University.

Papers
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Journal ArticleDOI
20 May 2015-Neuron
TL;DR: A structure-based approach is used to develop a new Gi-coupled DREADD using the kappa-opioid receptor as a template that is activated by the pharmacologically inert ligand salvinorin B (SALB) that robustly attenuated neuronal activity and modified behaviors.

306 citations

Journal ArticleDOI
TL;DR: An open-source suite of 14 optimized bioluminescence resonance energy transfer Gαβγ biosensors (named TRUPATH) to interrogate the transducerome with single pathway resolution in cells to enable a greater understanding of GPCR molecular pharmacology by the scientific community.
Abstract: G-protein-coupled receptors (GPCRs) remain major drug targets, despite our incomplete understanding of how they signal through 16 non-visual G-protein signal transducers (collectively named the transducerome) to exert their actions. To address this gap, we have developed an open-source suite of 14 optimized bioluminescence resonance energy transfer (BRET) Gαβγ biosensors (named TRUPATH) to interrogate the transducerome with single pathway resolution in cells. Generated through exhaustive protein engineering and empirical testing, the TRUPATH suite of Gαβγ biosensors includes the first Gα15 and GαGustducin probes. In head-to-head studies, TRUPATH biosensors outperformed first-generation sensors at multiple GPCRs and in different cell lines. Benchmarking studies with TRUPATH biosensors recapitulated previously documented signaling bias and revealed new coupling preferences for prototypic and understudied GPCRs with potential in vivo relevance. To enable a greater understanding of GPCR molecular pharmacology by the scientific community, we have made TRUPATH biosensors easily accessible as a kit through Addgene.

215 citations

Journal ArticleDOI
01 Aug 2016-Genesis
TL;DR: HM3Dq and hM4Di strains of mice are generated which allow for Cre recombinase‐mediated restricted expression of these pathway‐selective DREADDs, and these DREADD lines will be applicable to studying a wide array of research and preclinical questions.
Abstract: DREADDs, designer receptors exclusively activated by designer drugs, are engineered G protein-coupled receptors (GPCR) which can precisely control GPCR signaling pathways (for example, Gq, Gs, and Gi). This chemogenetic technology for control of GPCR signaling has been successfully applied in a variety of in vivo studies, including in mice, to remotely control GPCR signaling, for example, in neurons, glia cells, pancreatic β-cells, or cancer cells. In order to fully explore the in vivo applications of the DREADD technology, we generated hM3Dq and hM4Di strains of mice which allow for Cre recombinase-mediated restricted expression of these pathway-selective DREADDs. With the many Cre driver lines now available, these DREADD lines will be applicable to studying a wide array of research and preclinical questions. genesis 54:439-446, 2016. © 2016 Wiley Periodicals, Inc.

138 citations

Journal ArticleDOI
27 Jul 2018
TL;DR: DREADD agonist 21 (C21) (11-(1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) is a potent and selective agonist at both excitatory and inhibitory DREADDs and has excellent bioavailability, pharmacokinetic properties, and brain penetrability.
Abstract: Chemogenetic tools such as designer receptors exclusively activated by designer drugs (DREADDs) are routinely used to modulate neuronal and non-neuronal signaling and activity in a relatively noninvasive manner. The first generation of DREADDs were templated from the human muscarinic acetylcholine receptor family and are relatively insensitive to the endogenous agonist acetylcholine but instead are activated by clozapine-N-oxide (CNO). Despite the undisputed success of CNO as an activator of muscarinic DREADDs, it has been known for some time that CNO is subject to a low rate of metabolic conversion to clozapine, raising the need for alternative chemical actuators of muscarinic-based DREADDs. Here we show that DREADD agonist 21 (C21) (11-(1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) is a potent and selective agonist at both excitatory (hM3Dq) and inhibitory (hM4Di) DREADDs and has excellent bioavailability, pharmacokinetic properties, and brain penetrability. We also show that C21-induced activation of hM3Dq and hM4Di in vivo can modulate bidirectional feeding in defined circuits in mice. These results indicate that C21 represents an alternative to CNO for in vivo studies where metabolic conversion of CNO to clozapine is a concern.

121 citations

Journal ArticleDOI
24 Apr 2019-Nature
TL;DR: High-resolution room-temperature X-ray free electron laser structures of MT1 in complex with four agonists provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents.
Abstract: Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms1 by synchronization to environmental cues and is involved in diverse physiological processes2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function3. Melatonin is formed in the pineal gland in a light-regulated manner4 by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT1) and type 1B (MT2)3,6. Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden7. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids8,9, and is one of the most popular supplements in the United States10. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT1 in complex with four agonists: the insomnia drug ramelteon11, two melatonin analogues, and the mixed melatonin-serotonin antidepressant agomelatine12,13. The structure of MT2 is described in an accompanying paper14. Although the MT1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.

121 citations


Cited by
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01 Jan 2011
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

2,187 citations

Book ChapterDOI
01 Jul 2013
TL;DR: In this article, the authors discuss conflicts between ethics and law, regulations, or other governing legal authority, and present an informal resolution of these conflicts. But they do not address the problem of unfair discrimination.
Abstract: 1. Resolving Ethical Issues 1.01 Misuse of Psychologists’ Work 1.02 Conflicts Between Ethics and Law, Regulations, or Other Governing Legal Authority 1.03 Conflicts Between Ethics and Organizational Demands 1.04 Informal Resolution of Ethical Violations 1.05 Reporting Ethical Violations 1.06 Cooperating With Ethics Committees 1.07 Improper Complaints 1.08 Unfair Discrimination Against Complainants and Respondents

1,310 citations

Journal ArticleDOI
17 Feb 2016-Neuron
TL;DR: A primer on DREADDs is provided highlighting key technical and conceptual considerations and identify challenges for chemogenetics going forward.

1,145 citations

Journal ArticleDOI
TL;DR: The process of adult neurogenesis encompasses the proliferation of resident neural stem and progenitor cells and their subsequent differentiation, migration, and functional integration into the pre-existing circuitry.
Abstract: New neurons continue to be generated in two privileged areas of the adult brain: the dentate gyrus of the hippocampal formation and the olfactory bulb. Adult neurogenesis has been found in all mammals studied to date, including humans. The process of adult neurogenesis encompasses the proliferation of resident neural stem and progenitor cells and their subsequent differentiation, migration, and functional integration into the pre-existing circuitry. This article summarizes recent findings regarding the developmental steps involved in adult hippocampal neurogenesis and the possible functional roles that new hippocampal neurons might play.

717 citations

Journal ArticleDOI
TL;DR: This work describes the PEBL Test Battery, a set of approximately 70 behavioral tests which can be freely used, shared, and modified, and discusses the ethical factors involved in the open source testing movement.

709 citations