DOCSLIB.ORG

Intramolecular Allosteric Communication in Dopamine D2 Receptor Revealed by Evolutionary Amino Acid Covariation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Intramolecular Allosteric Communication in Dopamine D2 Receptor Revealed by Evolutionary Amino Acid Covariation Intramolecular allosteric communication in dopamine D2 receptor revealed by evolutionary amino acid covariation Yun-Min Sunga, Angela D. Wilkinsb, Gustavo J. Rodrigueza, Theodore G. Wensela,1, and Olivier Lichtargea,b,1 aVerna and Marrs Mclean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030; and bDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 Edited by Brian K. Kobilka, Stanford University School of Medicine, Stanford, CA, and approved February 16, 2016 (received for review August 19, 2015) The structural basis of allosteric signaling in G protein-coupled led us to ask whether ET could also uncover couplings among receptors (GPCRs) is important in guiding design of therapeutics protein sequence positions not in direct contact. and understanding phenotypic consequences of genetic variation. ET estimates the relative functional sensitivity of a protein to The Evolutionary Trace (ET) algorithm previously proved effective in variations at each residue position using phylogenetic distances to redesigning receptors to mimic the ligand specificities of functionally account for the functional divergence among sequence homologs distinct homologs. We now expand ET to consider mutual informa- (25, 26). Similar ideas can be applied to pairs of sequence positions tion, with validation in GPCR structure and dopamine D2 receptor to recompute ET as the average importance of the couplings be- (D2R) function. The new algorithm, called ET-MIp, identifies evolu- tween a residue and its direct structural neighbors (27). To measure tionarily relevant patterns of amino acid covariations. The improved the evolutionary coupling information between residue pairs, we predictions of structural proximity and D2R mutagenesis demon- present a new algorithm, ET-MIp, that integrates the mutual in- strate that ET-MIp predicts functional interactions between residue formation metric (MIp) (5) to the ET framework. We used dopa- pairs, particularly potency and efficacy of activation by dopamine. mine D2 receptor (D2R), a target of drugs for neurological and Remarkably, although most of the residue pairs chosen for mutagen- psychiatric diseases (28), to test whether ET-MIp could elucidate the esis are neither in the binding pocket nor in contact with each other, allosteric functional communications from amino acid covariation many exhibited functional interactions, implying at-a-distance cou- patterns and resolve the evolutionary distance at which the allosteric pling. The functional interaction between the coupled pairs corre- pathways of D2R homologs are sufficiently conserved to detect res- lated best with the evolutionary coupling potential derived from idue−residue coupling signatures. D2R is expressed in the central dopamine receptor sequences rather than with broader sets of GPCR nervous system and responds to dopamine, the major catecholamine sequences. These data suggest that the allosteric communication re- neurotransmitter. Canonical D2R signaling is effected by G class sponsible for dopamine responses is resolved by ET-MIp and best i/o G proteins, which regulate ion channels (29, 30), MAPK kinases discerned within a short evolutionary distance. Most double mutants restored dopamine response to wild-type levels, also suggesting that (31), phospholipase C (32), and inhibition of adenylyl cyclase (33). D1 class receptors (D1R and D5R) have lower affinities for tight regulation of the response to dopamine drove the coevolution – and intramolecular communications between coupled residues. Our dopamine (34 36) and activate adenylyl cyclase through Gs class G approach provides a general tool to identify evolutionary covariation proteins. To characterize allosteric communication between patterns in small sets of close sequence homologs and to translate them into functional linkages between residues. Significance allostery | G protein-coupled receptors | residue covariation | Characterizing relationships among protein structure, function, Evolutionary Trace and evolution requires understanding the evolutionary con- straints on each constituent residue of a protein. Previous dentifying residues that coevolved to maintain or acquire fit- studies have shown that structural information can be re- Iness properties is critical for understanding protein structure, trieved from evolutionary residue covariation in protein fami- function, and evolution (1). Previous studies have shown that lies. However, whether the evolutionary history in protein covarying residue pairs, those that exhibit correlated amino acid sequences informs on functional interactions between non- changes in large multiple sequence alignments, tend to form adjacent residues has been unclear. Here, we developed a structural contacts (2–7), enhancing predictions of protein 3D method that uses evolutionary amino acid covariation to infer BIOPHYSICS AND structures (8–11). Covariation can also involve distal residues, functionally coupled residue pairs in the dopamine D2 receptor. but the function of these at-a-distance couplings is elusive and We discovered functional coupling between residue pairs that COMPUTATIONAL BIOLOGY has been attributed to background noise, alternative protein have coevolved mainly to control responses to dopamine and conformations, or subunit interactions of protein homooligomers maintain them at wild-type levels. Our findings demonstrate the (5, 7, 12). Alternately, distal covarying residue pairs could in- possibility of extracting the networks of intramolecular allosteric dicate allosteric couplings (6, 13–18). communication from evolutionary residue covariation patterns. The possibility of capturing intramolecular allosteric communi- Author contributions: Y.S., A.D.W., T.G.W., and O.L. designed research; Y.S. and A.D.W. cation by amino acid covariation analysis of protein family se- performed research; Y.S., A.D.W., and G.J.R. contributed new reagents/analytic tools; Y.S., quences has not been extensively explored. Nonproximal A.D.W., T.G.W., and O.L. analyzed data; and Y.S., A.D.W., T.G.W., and O.L. wrote thermodynamic coupling between correlated residue pairs was the paper. noted in 274 PDZ domains (14), but the relationship to allo- The authors declare no conflict of interest. stery is still debated (19, 20). It may be that distinctive allosteric This article is a PNAS Direct Submission. mechanisms, even among close homologs, limit the extraction Freely available online through the PNAS open access option. of allosteric couplings from sequences (13). Our previous identi- 1To whom correspondence may be addressed. Email: [email protected] or twensel@ fication of residues important for allosteric signaling within G bcm.edu. protein-coupled receptors (GPCRs) using Evolutionary Trace (ET) This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (21–24) and strong conservation of some of the residues implicated 1073/pnas.1516579113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1516579113 PNAS | March 29, 2016 | vol. 113 | no. 13 | 3539–3544 Downloaded by guest on September 26, 2021 covarying pairs of residues ranked as important by ET (ET residue functional allostery in D2R, tuned to a specific ligand and sig- pairs), we examined functional coupling for ligand binding affinities naling bias, a more restricted alignment may be best. Accord- and downstream Gi activation induced by agonist-stimulated D2R. ingly, multiple alignments were tested (Class A, bioamine, dopamine, and D2Rs) and yielded distinct coupling scores Results (Table S2). ET-MIp Identified Pairs of Residue Positions with Evolutionary Covariation Patterns. We hypothesized that accounting for spe- Functional Interactions Between Covarying ET Residue Pairs Maintained cies divergence would improve the detection of functionally Dopamine Response at WT Level. To test whether the selected ET coupled residues over covariation analyses that ignore phyloge- residue pairs were functionally coupled, we first compared the netic information. ET-MIp adds the mutual information metric effects of single and double mutations on dopamine efficacy using (5) to ET to keep track of the phylogenetic distance at which a a fluorescence-based assay to study Gi activation induced by pair of residues vary (Fig. 1A; see Materials and Methods and agonist-stimulated D2R (Fig. 2; see Materials and Methods and Supporting Information for details). In ∼2,500 Class A GPCR Supporting Information for details). For five pairs (V83L2.53/ transmembrane (TM) domain sequences, we found that residue V91S2.61, M117F3.35/Y199F5.48, I48T1.46/F110W3.28,V152A4.42/ 4.61 3.42 5.54 pairs with high ET-MIp scores were more enriched for direct L171P , and N124H /T205M ), activation of Gi in re- contacts in a reference structure (PDB 2RH1) compared with sponse to dopamine was unexpectedly decreased or restored to a results obtained with leading alternative methods (5, 37, 38) (Fig. near-wild-type (WT) level in the double mutants, even though 1B), showing that GPCR phylogenetic information improves the one or both of the constituent single mutants showed signifi- coupling signal. Preliminary analysis of other protein families cantly enhanced response (Fig. 2 A and C). These results in- suggests that this result may be fairly general. This opens the dicate that covarying ET residue pairs help maintain dopamine possibility that ET-MIp also detects functionally relevant co- responses at the WT level. A trend was that functional coupling
Load more

Recommended publications
  • 309 Molecular Role of Dopamine in Anhedonia Linked to Reward
    [Frontiers In Bioscience, Scholar, 10, 309-325, March 1, 2018] Molecular role of dopamine in anhedonia linked to reward deficiency syndrome (RDS) and anti- reward systems Mark S. Gold8, Kenneth Blum,1-7,10 Marcelo Febo1, David Baron,2 Edward J Modestino9, Igor Elman10, Rajendra D. Badgaiyan10 1Department of Psychiatry, McKnight Brain Institute, University of Florida, College of Medicine, Gainesville, FL, USA, 2Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of South- ern California, Los Angeles, CA, USA, 3Global Integrated Services Unit University of Vermont Center for Clinical and Translational Science, College of Medicine, Burlington, VT, USA, 4Department of Addiction Research, Dominion Diagnostics, LLC, North Kingstown, RI, USA, 5Center for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purbe Medinpur, West Bengal, India, 6Division of Neuroscience Research and Therapy, The Shores Treatment and Recovery Center, Port St. Lucie, Fl., USA, 7Division of Nutrigenomics, Sanus Biotech, Austin TX, USA, 8Department of Psychiatry, Washington University School of Medicine, St. Louis, Mo, USA, 9Depart- ment of Psychology, Curry College, Milton, MA USA,, 10Department of Psychiatry, Wright State University, Boonshoft School of Medicine, Dayton, OH ,USA. TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Anhedonia and food addiction 4. Anhedonia in RDS Behaviors 5. Anhedonia hypothesis and DA as a “Pleasure” molecule 6. Reward genes and anhedonia: potential therapeutic targets 7. Anti-reward system 8. State of At of Anhedonia 9. Conclusion 10. Acknowledgement 11. References 1. ABSTRACT Anhedonia is a condition that leads to the loss like “anti-reward” phenomena. These processes of feelings pleasure in response to natural reinforcers may have additive, synergistic or antagonistic like food, sex, exercise, and social activities.
    [Show full text]
  • A Benchmarking Study on Virtual Ligand Screening Against Homology Models of Human Gpcrs
    bioRxiv preprint doi: https://doi.org/10.1101/284075; this version posted March 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. A benchmarking study on virtual ligand screening against homology models of human GPCRs Victor Jun Yu Lima,b, Weina Dua, Yu Zong Chenc, Hao Fana,d aBioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Matrix No. 07-01, 138671, Singapore; bSaw Swee Hock School of Public Health, National University of Singapore, 12 Science Drive 2, 117549, Singapore; cDepartment of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Singapore; dDepartment of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558 To whom correspondence should be addressed: Dr. Hao Fan, Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Matrix No. 07-01, 138671, Singapore; Telephone: +65 64788500; Email: [email protected] Keywords: G-protein-coupled receptor, GPCR, X-ray crystallography, virtual screening, homology modelling, consensus enrichment 1 bioRxiv preprint doi: https://doi.org/10.1101/284075; this version posted March 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2006/0052435 A1 Van Der Graaf Et Al
    US 20060052435A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0052435 A1 Van der Graaf et al. (43) Pub. Date: Mar. 9, 2006 (54) SELECTIVE DOPAMIN D3 RECEPTOR (86) PCT No.: PCT/GB02/05595 AGONSTS FOR THE TREATMENT OF SEXUAL DYSFUNCTION (30) Foreign Application Priority Data (76) Inventors: Pieter Hadewijn Van der Graaf, Dec. 18, 2001 (GB) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - O1302199 County of Kent (GB); Christopher Peter Wayman, County of Kent (GB); Publication Classification Andrew Douglas Baxter, Bury St. Edmunds (GB); Andrew Simon Cook, (51) Int. Cl. County of Kent (GB); Stephen A6IK 31/405 (2006.01) Kwok-Fung Wong, Guilford, CT (US) (52) U.S. Cl. .............................................................. 514/419 Correspondence Address: (57) ABSTRACT PFIZER INC. PATENT DEPARTMENT, MS8260-1611 The use of a composition comprising a Selective dopamine EASTERN POINT ROAD D3 receptor agonist, wherein Said dopamine D3 receptor GROTON, CT 06340 (US) agonist is at least about 15-times more functionally Selective for a dopamine D3 receptor as compared with a dopamine (21) Appl. No.: 10/499,210 D2 receptor when measured using the same functional assay, in the preparation of a medicament for the treatment and/or (22) PCT Filed: Dec. 10, 2002 prevention of Sexual dysfunction. Patent Application Publication Mar. 9, 2006 Sheet 1 of 2 US 2006/0052435 A1 Figure 1 A Selective D3 agonist provides a significant therapeutic window between prosexual and dose-limitind side effects Apomorphine EHV VE - vomiterection D27.2nMD33.9nM E HV H - hypotension O3 0.56nM Log Free plasma O. 1.0 O 1OO 1OOO conc (nM) D3D24973M agonist E noH noV D2 adOnist D2 ag Conclusion D3 No effect D2 & D3 mediates erection D2 mediates vomiting/hypotension Patent Application Publication Mar.
    [Show full text]
  • Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders
    biomolecules Review Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders Béla Kiss 1, István Laszlovszky 2, Balázs Krámos 3, András Visegrády 1, Amrita Bobok 1, György Lévay 1, Balázs Lendvai 1 and Viktor Román 1,* 1 Pharmacological and Drug Safety Research, Gedeon Richter Plc., 1103 Budapest, Hungary; [email protected] (B.K.); [email protected] (A.V.); [email protected] (A.B.); [email protected] (G.L.); [email protected] (B.L.) 2 Medical Division, Gedeon Richter Plc., 1103 Budapest, Hungary; [email protected] 3 Spectroscopic Research Department, Gedeon Richter Plc., 1103 Budapest, Hungary; [email protected] * Correspondence: [email protected]; Tel.: +36-1-432-6131; Fax: +36-1-889-8400 Abstract: Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome.
    [Show full text]
  • SZDB: a Database for Schizophrenia Genetic Research
    Schizophrenia Bulletin vol. 43 no. 2 pp. 459–471, 2017 doi:10.1093/schbul/sbw102 Advance Access publication July 22, 2016 SZDB: A Database for Schizophrenia Genetic Research Yong Wu1,2, Yong-Gang Yao1–4, and Xiong-Jian Luo*,1,2,4 1Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, China; 2Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China; 3CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China 4YGY and XJL are co-corresponding authors who jointly directed this work. *To whom correspondence should be addressed; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; tel: +86-871-68125413, fax: +86-871-68125413, e-mail: [email protected] Schizophrenia (SZ) is a debilitating brain disorder with a Introduction complex genetic architecture. Genetic studies, especially Schizophrenia (SZ) is a severe mental disorder charac- recent genome-wide association studies (GWAS), have terized by abnormal perceptions, incoherent or illogi- identified multiple variants (loci) conferring risk to SZ. cal thoughts, and disorganized speech and behavior. It However, how to efficiently extract meaningful biological affects approximately 0.5%–1% of the world populations1 information from bulk genetic findings of SZ remains a and is one of the leading causes of disability worldwide.2–4 major challenge. There is a pressing
    [Show full text]
  • Supplementary Table 2
    Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942
    [Show full text]
  • Distribution of Dopamine D3 Receptor Expressing Neurons in the Human Forebrain: Comparison with D2 Receptor Expressing Neurons Eugenia V
    Distribution of Dopamine D3 Receptor Expressing Neurons in the Human Forebrain: Comparison with D2 Receptor Expressing Neurons Eugenia V. Gurevich, Ph.D., and Jeffrey N. Joyce, Ph.D. The dopamine D2 and D3 receptors are members of the D2 important difference from the rat is that D3 receptors were subfamily that includes the D2, D3 and D4 receptor. In the virtually absent in the ventral tegmental area. D3 receptor rat, the D3 receptor exhibits a distribution restricted to and D3 mRNA positive neurons were observed in sensory, mesolimbic regions with little overlap with the D2 receptor. hormonal, and association regions such as the nucleus Receptor binding and nonisotopic in situ hybridization basalis, anteroventral, mediodorsal, and geniculate nuclei of were used to study the distribution of the D3 receptors and the thalamus, mammillary nuclei, the basolateral, neurons positive for D3 mRNA in comparison to the D2 basomedial, and cortical nuclei of the amygdala. As revealed receptor/mRNA in subcortical regions of the human brain. by simultaneous labeling for D3 and D2 mRNA, D3 mRNA D2 binding sites were detected in all brain areas studied, was often expressed in D2 mRNA positive neurons. with the highest concentration found in the striatum Neurons that solely expressed D2 mRNA were numerous followed by the nucleus accumbens, external segment of the and regionally widespread, whereas only occasional D3- globus pallidus, substantia nigra and ventral tegmental positive-D2-negative cells were observed. The regions of area, medial preoptic area and tuberomammillary nucleus relatively higher expression of the D3 receptor and its of the hypothalamus. In most areas the presence of D2 mRNA appeared linked through functional circuits, but receptor sites coincided with the presence of neurons co-expression of D2 and D3 mRNA suggests a functional positive for its mRNA.
    [Show full text]
  • Implications of Dopamine D3 Receptor for Glaucoma: In-Silico and In-Vivo Studies
    International PhD Program in Neuropharmacology XXVI Cycle Implications of dopamine D3 receptor for glaucoma: in-silico and in-vivo studies PhD thesis Chiara Bianca Maria Platania Coordinator: Prof. Salvatore Salomone Tutor: Prof. Claudio Bucolo Department of Clinical and Molecular Biomedicine Section of Pharmacology and Biochemistry. University of Catania - Medical School December 2013 Copyright ©: Chiara B. M. Platania - December 2013 2 TABLE OF CONTENTS ACKNOWLEDGEMENTS............................................................................ 4 LIST OF ABBREVIATIONS ........................................................................ 5 ABSTRACT ................................................................................................... 7 GLAUCOMA ................................................................................................ 9 Aqueous humor dynamics .................................................................. 10 Pharmacological treatments of glaucoma............................................ 12 Pharmacological perspectives in treatment of glaucoma ..................... 14 Animal models of glaucoma ............................................................... 18 G PROTEIN COUPLED RECEPTORS ....................................................... 21 GPCRs functions and structure ........................................................... 22 Molecular modeling of GPCRs ........................................................... 25 D2-like receptors ...............................................................................
    [Show full text]
  • Co-Regulation of Hormone Receptors, Neuropeptides, and Steroidogenic Enzymes 2 Across the Vertebrate Social Behavior Network 3 4 Brent M
    bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Co-regulation of hormone receptors, neuropeptides, and steroidogenic enzymes 2 across the vertebrate social behavior network 3 4 Brent M. Horton1, T. Brandt Ryder2, Ignacio T. Moore3, Christopher N. 5 Balakrishnan4,* 6 1Millersville University, Department of Biology 7 2Smithsonian Conservation Biology Institute, Migratory Bird Center 8 3Virginia Tech, Department of Biological Sciences 9 4East Carolina University, Department of Biology 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Running Title: Gene expression in the social behavior network 2 Keywords: dominance, systems biology, songbird, territoriality, genome 3 Corresponding Author: 4 Christopher Balakrishnan 5 East Carolina University 6 Department of Biology 7 Howell Science Complex 8 Greenville, NC, USA 27858 9 [email protected] 10 2 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Kenneth Martin Rosenberg Email: [email protected], [email protected] 660 West Redwood Street, Howard Hall Room 332D, Baltimore, MD, 21201
    The impact of the non-immune chemiome on T cell activation Item Type dissertation Authors Rosenberg, Kenneth Publication Date 2020 Abstract T cells are critical organizers of the immune response and rigid control over their activation is necessary for balancing host defense and immunopathology. It takes 3 signals provided by dendritic cells (DC) to fully activate a T cell response – T ce... Keywords signaling; T cell; T-Lymphocytes--immunology Download date 02/10/2021 13:41:58 Link to Item http://hdl.handle.net/10713/14477 Kenneth Martin Rosenberg Email: [email protected], [email protected] 660 West Redwood Street, Howard Hall Room 332D, Baltimore, MD, 21201 EDUCATION MD, University of Maryland, Baltimore, MD Expected May 2022 PhD, University of Maryland, Baltimore, MD December 2020 Graduate Program: Molecular Microbiology and Immunology (MMI) BS, University of Maryland, College Park, MD May 2013 Major: Bioengineering, cum laude University Honors Citation, Gemstone Citation RESEARCH EXPERIENCE UMSOM Microbiology and Immunology Baltimore, MD July 2016-present PhD Candidate Principal Investigator: Dr. Nevil Singh Thesis: The impact of the non-immune chemiome on T cell activation Examined environmental stimuli from classically “non-immune” sources – growth factors, hormones, neurotransmitters, etc. – act to modulate T cell signaling pathways and the functional effects of activating encounters with dendritic cells. UMSOM Anatomy and Neurobiology Baltimore, MD May-August 2015 Rotating student Principal Investigator: Dr. Asaf Keller Studied the role of descending modulation pathways on affective pain transmission. Performed tract- tracing experiments using targeted injection of Cholera toxin subunit B into the lateral parabrachial nucleus and ventrolateral periaqueductal gray of anesthetized transgenic mice.
    [Show full text]
  • Conversion of the Modulatory Actions of Dopamine on Spinal Reflexes
    The Journal of Neuroscience, December 15, 2004 • 24(50):11337–11345 • 11337 Behavioral/Systems/Cognitive Conversion of the Modulatory Actions of Dopamine on Spinal Reflexes from Depression to Facilitation in D3 Receptor Knock-Out Mice Stefan Clemens and Shawn Hochman Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322 Descending monoaminergic systems modulate spinal cord function, yet spinal dopaminergic actions are poorly understood. Using the in vitro lumbar cord, we studied the effects of dopamine and D2-like receptor ligands on spinal reflexes in wild-type (WT) and D3-receptor knock-out mice (D3KO). ␮ Low dopamine levels (1 M) decreased the monosynaptic “stretch” reflex (MSR) amplitude in WT animals and increased it in D3KO animals. Higher dopamine concentrations (10–100 ␮M) decreased MSR amplitudes in both groups, but always more strongly in WT. Like low dopamine, the D3 receptor agonists pergolide and PD 128907 reduced MSR amplitude in WT but not D3KO mice. Conversely, D3 receptor antagonists (GR 103691 and nafadotride) increased the MSR in WT but not in D3KO mice. In comparison, D2-preferring agonists bromocriptine and quinpirole depressed the MSR in both groups. Low dopamine (1–5 ␮M) also depressed longer-latency (presumably ␮ polysynaptic) reflexes in WT but facilitated responses in D3KO mice. Additionally, in some experiments (e.g., during 10 M dopamine or pergolide in WT), polysynaptic reflexes were facilitated in parallel to MSR depression, demonstrating differential modulatory control of these reflex circuits. Thus, low dopamine activates D3 receptors to limit reflex excitability. Moreover, in D3 ligand-insensitive mice, excitatory actions are unmasked, functionally converting the modulatory action of dopamine from depression to facilitation.
    [Show full text]
  • Effects of Cocaine on D2 and D3 Dopamine Receptor Expression And
    EFFECTS OF COCAINE ON D2 AND D3 DOPAMINE RECEPTOR EXPRESSION AND FUNCTION IN THE RAT BRAIN by XIAOYA CHEN (Under the Direction of Shelley B. Hooks) ABSTRACT D2 and D3 receptors are subtypes of D2-like dopamine receptors, and both have been shown to be involved in drug addiction with different roles. Their mRNA are expressed moderately highly in striatum, where dopamine plays a crucial role in drug reward pathways, and are expressed at low level in hippocampus, where dopamine has recently been implicated in the long-term, memory components of addiction. In our studies, we did functional and gene expression assays on dorsal and ventral fractions of striatum and hippocampus from eight cocaine-treated and control rats. We found that the potency of D2/D3 receptor agonist was highest in dorsal striatum. The potency of receptor activity was more correlated with D2 receptor gene expression than D3 receptor expression. Cocaine did not show any convincing effect on D2 and D3 receptor function and gene expression. INDEX WORDS: D2-like dopamine receptors, D2 dopamine receptor, D3 dopamine receptor, Cocaine, Addiction, Dorsal striatum, Ventral striatum, Dorsal hippocampus, Ventral hippocampus EFFECTS OF COCAINE ON D2 AND D3 DOPAMINE RECEPTOR EXPRESSION AND FUNCTION IN THE RAT BRAIN by XIAOYA CHEN BENG, China Pharmaceutical University, China, 2004 A Thesis Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCES ATHENS, GEORGIA 2008 © 2008 Xiaoya Chen All Rights Reserved EFFECTS OF COCAINE ON D2 AND D3 DOPAMINE RECEPTOR EXPRESSION AND FUNCTION IN THE RAT BRAIN by XIAOYA CHEN Major Professor: Shelley B.
    [Show full text]