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  1. Alcoholism and GRM7 Jennifer Wagner Image from

  2. Alcoholism – The Disease Due to an imbalance in neurotransmitter levels leading to… 1) Cravings 2) Loss of control 3) Withdrawal 4) Tolerance Video Mayo Foundation for Medical Education and Research (MFMER), 2008 Image from

  3. Alcoholism – Risk Factors Emotional state Psychological factors Social and cultural factors Age, sex Genetics (including GRM7) Mayo Foundation for Medical Education and Research (MFMER), 2008 Images from,

  4. Vadasz et al. 2007 Discovered link between alcoholism and GRM7 Lowered GRM7 expression correlated to increased preference for alcohol Image from

  5. Alcoholism – Why study the genes involved? Affects 1 in 12 Americans Leads to damaged relationships, financial problems, and unemployment, as well as severe health problems Understanding the genetic causes may lead to development of better prevention as well as new drug treatments Mayo Foundation for Medical Education and Research (MFMER), 2008 Image from

  6. GRM7 G-protein coupled metabotropic glutamate receptor: ANF domain: extra-cellular ligand binding NCDG3: stable linker composed of disulphide bridges 7tm_3: transmembrane region, signal transducer SMART database

  7. Gene Ontology Biological Processes: synaptic transmission, conditioned taste aversion, learning and memory, behavioral fear response, transmission of nerve impulse, multicellular organismal response to stress Cellular Components: integral to plasma membrane, postsynaptic membrane, presynaptic active zone Molecular Functions: glutamate binding, calmodulin binding, calcium channel regulator, PDZ domain binding AmiGO database

  8. Expression Patterns Oscar-Berman and Marinkovic, 2003.

  9. MicroArray data Samples from post-mortem humans averaging 70 yrs GRM7 expression shown to be lower in males GEO database; Rinn, et al., 2004

  10. GRM7 Homologs Entrez Protein database; Anisimova, et al., 2006; Castresana, 2000; Chevenet, et al., 2008; Dereeper, et al., 2008; Guindon, et al., 2003; Notredame, et al., 2000

  11. GRM7 Homologs Homo sapiens GRM7 Mus musculus Grm7 – 99% identity Rattus norvegicus Grm7 – 99% identity Drosophila melanogaster mGluRA – 47% identity Caenorhabditis elegans mgl-1 – 38% identity Entrez Protein database; Altschul, et al., 2005; Altschul, et al., 1997 Images from Pfam database

  12. RNAi C. elegans – mgl-1 post-embryonic slow-growth rate D. melanogaster – mGluRA neurophysiological defects in presynaptic excitability and synaptic morphology Wormbase; Kamath, et al., 2003; Flybase; Bogdanik, 2004 Images from,

  13. Chemical Genetics AMN082 – a selective GRM7 agonist: caused decreased alcohol preference in mice MMPIP – a selective GRM7 antagonist: potential for use in future studies AMN082 MMPIP Tocris bioscience, 2009; Salling, et al., 2008; Suzuki, et al., 2007; Flor, et al., 2008; Mitsukawa, et al., 2005

  14. Protein Interactions Text-mining evidence Experimental evidence STRING database

  15. Protein Interactions - Similarities PICK1 PKCA CAM3 MARKSL1 SYN47 Vesl-2 SMART database

  16. Future Directions IP followed by mass spectrometry to confirm predicted protein interactions Exploring protein interactions MicroArray studies in post- mortem samples from human alcoholics vs. non-alcoholics Image from

  17. Conclusions Lowered expression of GRM7 correlates to increased susceptibility to alcoholism GRM7 may not be a good target for therapeutic intervention in alcoholism However, learning more about it may lead to useful treatments Image from

  18. Questions?

  19. References -Literature Altschul, S.F., Madden, T. L., Schäffer, A. A., Zhang, J., Zhang, Z., Miller, W., and Lipman, D. J. (1997). Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Research, 25:3389-3402. Altschul, S. F., Wootton, J. C., Gertz, E. M., Agarwala, R., Morgulis, A., Schäffer, A. A., and Yu, Y. K. (2005). Protein database searches using compositionally adjusted substitution matrices. FEBS J., 272:5101-5109. Bogdanik, L., Mohrmann, R., Ramaekers, A., Bockaert, J., Grau, Y., Broadie, K., Parmentier, M.L. (2004). The Drosophila metabotropic glutamate receptor DmGluRA regulates activity-dependent synaptic facilitation and fine synaptic morphology.  J. Neurosci. 24(41): 9105--9116. Castresana J. (2000). Selection of conserved blocks from multiple alignments for their use in phylogenetic analysis. Mol Biol Evol. 17(4):540-52. Chevenet F., Brun C., Banuls AL., Jacq B., Chisten R. (2008) TreeDyn: towards dynamic graphics and annotations for analyses of trees. BMC Bioinformatics. 7:439. Dereeper A.*, Guignon V.*, Blanc G., Audic S., Buffet S., Chevenet F., Dufayard J.F., Guindon S., Lefort V., Lescot M., Claverie J.M., Gascuel O. (2008). robust phylogenetic analysis for the non-specialist. Nucleic Acids Res. 36(Web Server issue):W465-9. *joint first authors Flor, P.J., Vassout, A., Fendt, M., Mitsukawa, K., Jacobson, L., Yamamoto, R., Nozulak, J., Ofner, S., Pescott, O., Lukic, S., Stoehr, N., Urwyler, S., Kuhn, R., Herrling, P., McAllister, K., van der Putten, H., and Cryan, J.F. (2005). AMN082, the first selective mGluR7 agonist: activation of receptor signaling via an allosteric site in the transmembrane domain modulates stress parameters in vivo. [Abstract]. Neuropharmacology, 49 (Suppl. 1):244. doi: 10.1016/j.neuropharm.2005.06.013 Guindon S., Gascuel O. (2003). A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst Biol. 52(5):696-704. Kamath, R.S., Fraser, A.G., Dong, Y., Poulin, G., Durbin, R., Gotta, M., Kanapin, A., Le Bot, N., Moreno, S., Sohrmann, M., Welchman, D.P., Zipperlen, P., Ahringer, J. (2003). Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature, 421(6920):231-7. doi:10.1038/nature01278 Mayo Foundation for Medical Education and Research (MFMER). (2008, May 8). Alcoholism. Retrieved February 2, 2009, from

  20. References -Literature Mitsukawa, K., Yamamoto, R., Ofner, S., Nozulak, J., Pescott, O., Lukic, S., Stoehr, N., Mombereau, C., Kuhn, R.,  McAllister, K., van der Putten, H., Cryan, J.F., and Flor, P.J. (2005). A selective metabotropic glutamate receptor 7 agonist: Activation of receptor signaling via an allosteric site modulates stress parameters in vivo. Proc. Natl. Acad. Sci. USA ,102(51):18712. doi: 10.1073/pnas.0508063102. Notredame C., Higgins DG., Heringa J. (2000). T-Coffee: A novel method for fast and accurate multiple sequence alignment. J Oscar-Berman, M. and Marinkovic, K. (2003). Alcoholism and the brain: An overview. Alcohol Research and Health, 27(2), 125. Retrieved February 2, 2009, from: Rinn, J.L., Rozowsky, J.S., Laurenzi, I.J., Petersen, P., Zon, K., Zhong, W., Gerstein, M., Snyder, M.P. (2004). Sex Specific Transcription in Human Hypothalamus. Retrieved April 22, 2009 from$&gmin=24.600000&gmax=750.500000&absc=19194p2p1p1p1p3p1p3p3p3&gds=564&idref=207548_at&annot=GRM7 Salling, M.C., Faccidomo, S., Hodge, C.W. (2008). Nonselective suppression of operant ethanol and sucrose self-administration by the mGluR7 positive allosteric modulator AMN082. Pharmacology Biochemistry and Behavior, 91(1):14. doi: 10.1016/j.pbb.2008.06.006  Suzuki, G., Tsukamoto, N., Fushiki, H., Kawagishi, A., Nakamura, M., Kurihara, H., Mitsuya, M., Ohkubo, M., and Ohta, H. (2007). In Vitro Pharmacological Characterization of Novel Isoxazolopyridone Derivatives as Allosteric Metabotropic Glutamate Receptor 7 Antagonists . J Pharmacol Exp Ther, 323(1):147. doi: 10.1124/jpet.107.124701 Tocris Bioscience. (2009). AMN082 dihydrochloride. Retrieved May 2, 2009, from Tocris Bioscience. (2009). MMPIP hydrochloride. Retrieved May 3, 2009, from Vadasz, C., Saito, M., Gyetvai, B. M., Oros, M., Szakall, I., Kovacs, K. M., Prasad, V. V. T. S., Toth, R. (2007). Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking. Genomics, 90(6):690. doi:10.1016/j.ygeno.2007.08.006

  21. References - Databases AmiGO: Entrez Protein: Flybase: GEO: Pfam: SMART: STRING: Wormbase: