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Scripps Research Joint Appointments

Associate Professor, Department of Neuroscience
Faculty, Kellogg School of Science and Technology

Research Focus

G protein coupled receptor (GPCR) signaling is regulated by β-arrestins. β-arrestins are intracellular scaffolding proteins that bind to and regulate activated receptors. The β-arrestins either prevent or enhance GPCR coupling to intracellular signaling molecules. Our work has shown that the role a β-arrestin plays in vivo depends upon the chemical structure of the agonist as well as the location of the receptor. In other words, β-arrestins may turn off signaling of a receptor in one tissue, but may facilitate signaling in another. Further, one agonist may elicit the dampening effects of βarrestins while another agonist may promote a pro-signaling interaction with β-arrestins.

Our primary interest is in understanding how the regulation of GPCRs can ultimately determine physiological responsiveness to neurotransmitters and pharmaceutics in vivo. We utilize multidisciplinary approaches to assess drug-induced changes in behaviors and physiologies, which we then link to altered receptor-mediated signal transduction cascades in tissues and in primary cultures. Our ultimate goal is to improve drug therapy and to eliminate side effects. We have two major receptor focus areas:

1. We assess opioid receptor function to determine how these receptors can be tweaked to improve pain therapy. Our efforts focus on dissecting receptor regulation in vivo. This may prove to be a pivotal point at which we can fine-tune receptor signaling to improve pain relief while preventing tolerance, dependence, addiction, respiratory suppression and constipation.
2. We study serotonin 2A receptors to determine how they may function differently in response to serotonin versus compounds that induce hallucinations with the hopes of improving treatment options for depression and schizophrenia.

 We are very interested in drug development and work closely with medicinal and synthetic chemists as well as researcher in the Drug Discovery group at TSRI.

Education

B.S., Biochemistry, Virginia Polytechnic Institute and State University, 1993
Ph.D., Biochemistry & Molecular Biology, Saint Louis University, 1999
B.A., Chemistry, Virginia Polytechnic Institute and State University, 1993

Awards & Professional Activities

The John J. Abel Award from the American Society of Pharmacology & Experimental Therapeutics and Pfizer (06/11).
MiniReview editro, Molecular Pharmacology (2010-2012)
Co-Founder, Mencuro Therapeutics, Inc. 12/10
Roundtable Discussant and Speaker, Neuropharmacology Conference: High Resolution Neuropharmacology: Structure Changes the Paradigm. 11/10
The Joseph Cochin Young Investigator Award from the College on Problems of Drug Dependence 6/09
NIH ZRG1 MDCN-Molecular Neuropharmacology and Signaling Study Section (MNPS) Member (2009-2013)
Featured as one of “30 in Their 30s” by BioOhio, “The Voice of Bioscience in Ohio” 5/07.
School of Biomedical Sciences Award for Excellence in Research, The Ohio State University 9/06 2005
2005 Committee on Women in Neuroscience Career Development Award, sponsored by the Society for Neuroscience and Merck 11/05.
College on Problems of Drug Dependence Early Career Investigator Award 6/02
Postdoctoral Research Award, Joint University of North Carolina - Chapel Hill and Duke University Cell and Developmental Biology Retreat 4/02
Ruth L. Kirschstein National Research Service Award (NRSA) Postdoctoral Fellowship (NIDA F32, 4/00-4/02)
Ruth L. Kirschstein National Research Service Award (NRSA) Predoctoral Fellowship (NIDA F31, 4/96-4/99)
Student Representative to University Board of Governors 8/97-6/98
President, Graduate Student Association 8/97-8/98
Graduate Student Association Award for Research Excellence 3/96
Vice President, Graduate Student Association 8/96-8/97
Graduation: Cum Laude, VA Tech. 5/93

Selected References

Zhou H. Chisari M, Raehal KM, Kaltenbronn KM, Bohn LM, Mennerick SJ, Blumer KJ. GIRK channel modulation by assembly with allosterically regulated RGS proteins. Proc Natl Acad Sci USA. 2012 Dec 4;109(49):19977-82. doi: 10.1073/pnas.1214337109. Epub 2012 Nov 19.
PMID: 23169654 [PubMed - indexed for MEDLINE]

Nguyen PT, Schmid CL, Raehal KM, Selley DE, Bohn LM, Sim-Selley LJ. β-arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region-dependent manner. Biol Psychiatry 2012 Apr 15;71(8):714-24. doi:10.1016/j.biopsych.2011.11.128. Epub 2012 Jan 20.
PMID: 22264443 [PubMed - indexed for MEDLINE]

Frankowski KJ, Hedrick MP, Gosalia P, Li K, Shi S, Whipple D, Ghosh P, Prisinzano TE, Schoenen FJ,
Su Y, Vasile S, SergientoE, Gray W, Hariharan S, Milan L, Heynen-Genel S, Mangravita-Nova A,
Vicchiarelli M, Smith LH, Streicher JM, Caron MG, Barak LS, Bohn LM, Chung TD, Aube J. Discovery
of Small Molecule Kappa Opioid Receptor Agonist and Antagonist Chemotypes through a HTS and
Hit Refinement Strategy. ACS Chem Neurosci. 2012 Mar 21;3(3):221-236. Epub 2012 Jan 20.
PMID: 22737280 [PubMed]

Lamb K, Tidgewell K, Simpson DS, Bohn LM, Prisinzano TE. Antinociceptive effects of herkinorin, a MOP receptor agonist derived from salvinorin A in the formalin test in rats: new concepts in mu opioid receptor pharmacology: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend. 2012 Mar 1;121(3):181-8. doi: 10.1016/j.drugalcdep.2011.10.026. Epub 2011 Nov 26.
PMID: 22119134 [PubMed - indexed for MEDLINE]

Beguin C, Potuzak J, Xu W, Liu-Chen LY, Stricher JM, Groer CE, Bohn LM, Carlezon WA Jr, Cohen BM. Differential signaling properties at the kappa opioid receptor of 12-epi-salvinorin A and its analogues. Biorg Med Chem Lett. 2012 Jan 15;22(2):1023-6. doi: 10.1016/j.bmcl.2011.11.128.Epub 2011 Dec 7.
PMID: 22204910 [PubMed - indexed for MEDLINE]

Raehal KM, Schmid CL*, Groer CE*, Bohn LM. Functional selectivity at the mu opioid receptor: Implications for understanding opiate analgesia and tolerance. Pharmaco. Rev. 2011 Dec; 63(4):1001-19. doi: 10.1124/pr.111.004598. Epub 2011 Aug 26. Review.
PMID: 21873412 [PubMed - indexed for MEDLINE]

Groer CE*, Schmid CL*, Jaeger AM, and Bohn LM.   Agonist-directed interactions with specific beta-arrestins determine mu opioid receptor trafficking, ubiquitination, and dephosphorylation J Biol, chem. 2011 Sep 9;286(36):31731-41. doi: 10.1074/jbc.M111.248310. Epub 2011 Jul 14.
PMID: 21757712 [PubMed - indexed for MEDLINE]

Tarselli MA, Raehal KM, Brasher AK, Streicher JM, Groer CE*, Cameron MD, Bohn LM^ and Micalizio GC^. Synthesis of conolidine, a Potent Non-opioid Analgesic for Tonic and Persistent Pain. Nature Chemistry, 2011 Jun;3(6)::449-453. doi: 10.1038/nchem.1050.
PMID: 21602859. [PubMed - indexed for MEDLINE]

Raehal KM and Bohn LM.  The role of beta-arrestin2 in the severity of antinociceptive tolerance and physical dependence induced by different opioid pain therapeutics. Neuropharmacology. Special Issue-  " When Structure Meets Function". 2011 Jan;60(1):58-65. doi: 10.1016/j.neuropharm.2010.08.003.Epub 2010 Aug 14.
PMID: 20713067 [PubMed - indexed for MEDLINE]

Hedrick MP, Gosalia P, Li K, Frankowski KJ, Shi S, Prisinzano TE, Schoenen F, aube J, Su Y, Stonich D, Vasile S, Sergienko E, Gray W, Hariaharan S, Milan L, Heynen-Genel S, Vicchiarelli M, Margravita-Novo A, Streicher JM, Smith LH, Chung TDY, Caron M, Bohn LM, Barak LS. Selective KOP Receptor Antagonists: Probe 1 & Probe 2. Probe reports from the NIH Molecular Libraries Program {internet}. Bethesda (MD): National Center for Biotechnology Information (US);2010-. 2010 Feb 28[updated 2010 Oct 4].
PMID: 21433386 [PubMed] 

Hedrick MP, Gosalia P, Frankowski K, Shi S, Prisinzano TE, Schoenen F, Aube J, Su Y, Vasile S, Sergienko E, Gray W, Hariharan S, ghosh P, Milan L, Heynen-Genel S, Chung TDY, Dad S, Caron M, Bohn LM, Barak LS. Selective KOP Receptor Antagonists: Probe 1. Probe Reports from the NIH Molecular Libraries Program [internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. 2010 Feb 28 [updated 2010 Oct 4]
PMID: 21433381 [PubMed]

Bohn LM, McDonald PH. Seeking Ligand Bias: Assessing GPCR Coupling to Beta-Arrestins for Drug Discovery. Invited Review for  Drug Discovery Today: Technologies, Theme issue: Mechanistic Pharmacology, new developments.2010 Spring; 7(1):e37-e42.
PMID: 21218149 [PubMed]

Sun X, Wang X, Wang GD, Xia Y, Liu S, Qu M, Needleman Bj, Mikami DJ, Melvin WS, Bohn LM, Ueno R, Wood JD. Lubiprostone reverses the inhibitory action of morphine on mucosal secretion in human small intestine. Dig Dis Sci. 2011 Feb;56(2):330-8. doi: 10.1007/s10620-010-1515-8. Epub 2010 Dec 23.
PMID: 21181441 [PubMed - indexed for MEDLINE]

Bohn, LM and Schmid, CL*.  Serotonin Receptors Signaling and Regulation via Beta Arrestins. Critical Reviews biochem. and Mol. Biol.  2010 Dec;45(6):555-66. doi:10.3109/10409238.2010.516741. Epub 2010 Oct 7. Review.
PMID: 20925600 [PubMed - indexed for MEDLINE]

Schmid, LC* and Bohn, LM. (2010) Serotonin, but not N-Methyltryptamines, activates the Serotonin 2A Receptor via a Beta Arrestin2/Src/Akt signaling complex in vivo. Journal of Neuroscience. 2010 Oct 6;30(40):13513-24. doi: 10.1523/JNEUROSCI.1665-10.2010.
PMID: 20926677 [PubMed - indexed for MEDLINE]

Bohn, LM and McDonald PH.  Seeking Ligand bias: Assessing GPCR Coupling to Beta-Arrestins for Drug Discovery.  Invited Review for  Drug Discovery Today: Technologies, Theme issue: Mechanistic Pharmacology, new developments. 2010 Spring;7(1):e37-242.

Schmid CL, Bohn LM. (2009). Physiological and pharmacological implications of beta-arrestin regulation. Pharmacol Ther.121(3):285-93.

Schmid CL, Raehal KM, Bohn LM. (2008). From the Cover: Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo. Proc Natl Acad Sci U S A.105(3):1079-84.

Bohn LM, Raehal KM. (2006). Opioid receptor signaling: relevance for gastrointestinal therapy. Curr Opin Pharmacol.6(6):559-63.

Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG. (2000). Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature.408(6813):720-3.

Bohn, L. M. “Selectivity for G Protein or Arrestin-Mediated Signaling” in Functional Selectivity of GPCR Ligands. (Ed. K. Neve) Humana Press, Totowa, 2009, pp. 71-85.

Raehal KM, Schmid CL, Medvedev IO, Gainetdinov RR, Premont RT, Bohn LM. (2009). Morphine-induced physiological and behavioral responses in mice lacking G protein-coupled receptor kinase 6. Drug Alcohol Depend. 104(3):187-96.

Tidgewell K, Groer CE, Harding WW, Lozama A, Schmidt M, Marquam A, Hiemstra J, Partilla JS, Dersch CM, Rothman RB, Bohn LM, Prisinzano TE. (2008). Herkinorin analogues with differential beta-arrestin-2 interactions. J Med Chem.51(8):2421-31.

Groer CE, Tidgewell K, Moyer RA, Harding WW, Rothman RB, Prisinzano TE, Bohn LM. (2007). An opioid agonist that does not induce mu-opioid receptor-β-arrestin interactions or receptor internalization. Mol Pharmacol.71(2):549-57.

Raehal KM, Walker JK, Bohn LM. (2005). Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther.314(3):1195-201.

Bohn LM, Dykstra LA, Lefkowitz RJ, Caron MG, Barak LS. (2004). Relative opioid efficacy is determined by the complements of the G protein-coupled receptor desensitization machinery. Mol Pharmacol.66(1):106-12.

Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. (1999). Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science.286(5449):2495-8.

Links

Scripps Florida's Laura Bohn Wins 2009 Joseph Cochin Young Investigator Award

Researchers Shed Light on How Serotonin Works

Scripps Research Scientist Wins Prestigious John J. Abel Award in Pharmacology

Led by advances in Chemical Synthsis, Scripps Research Scientists discover that a rare Natural product has potent pain-killing properties

Medicinal Chemistry: New lead for pain treatment

Compound Offers Pain Relief without the Complications

Natural Pain-Killing Chemical Synthesized: Making conolidine in the lab could further drug research

Natural Product Kills Pain, But How?