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Laura M. Bohn, Ph.D.

Professor
Department of Molecular Medicine
Florida Campus
Scripps VIVO Scientific Profile
lbohn@scripps.edu
(561) 228-2227

Scripps Research Joint Appointments

Associate Professor, Department of Neuroscience
Faculty, Graduate Program

Research Focus

Research in the Bohn laboratory is focused on understanding how G protein-coupled receptors function in an endogenous setting to control physiologically relevant processes.  We are most interested in receptors that mediate neurological functions, particularly those of the opioid, serotonin and cannabinoid families.  Ultimately, our goal is to refine therapeutics- to enhance the benefits and eliminate the side effects.  In this manner, we hope to inspire new approaches in treating pain, addiction and mood disorders.

 The Bohn laboratory is most widely known for our work in opioid receptors.  Early work while in the laboratory of Marc Caron and in collaboration with Robert Lefkowitz at Duke University indicated that barrestin2 plays a critical role in determining the physiological role of the mu opioid receptor (MOR) in vivo.  Our laboratory has shown that barrestin2 plays different roles in regulating the MOR depending upon the physiological function assessed.  This is very important as activation of the MOR results in multiple physiological processes ranging from the highly desirable suppression of pain perception to the deadly effects of respiratory failure.  By determining which barrestin2-mediated signaling pathways are associated with these different physiological outcomes, we aim to elucidate a means to develop potent opioid analgesics that circumvent the adverse side effects.  The bulk of our work to date suggests that if we preserve MOR coupling to G proteins, but eliminate the interactions between the receptor and the scaffolding protein, barrestin2, then we may be able to separate analgesic potency from constipation, respiratory suppression, tolerance and physical dependence.

Our lab is now focused on developing tool compounds that will allow us to test these hypotheses. Our agonists are designed, in collaboration with Dr. Tom Bannister of TSRI, to activate MOR in a manner that preserves or improves G protein signaling while eliminating the recruitment of barrestins. In addition to generating potential therapeutic leads, we are very interested in using these tools to elucidate MOR function in vivo. As we refine the pathways underlying different physiological responses, we will then know the signaling mechanisms to preserve and the ones to avoid. 

We are also taking a similar approach with the kappa opioid receptors (KOR). The KOR in the midbrain acts to regulate dopamine and serotonin levels and thereby serves as an attractive target for modulating mood and reward thresholds. KOR ligands that display bias towards or against recruiting barrestins are of interest as barrestin2 has been implicated in facilitating aversive KOR-mediated behaviors. In our work with Dr. Jeff Aubé of Kansas University, we have been developing and evaluating KOR biased agonists to determine which physiologies are preserved or disrupted in mouse models. Since the KOR is involved in diverse physiological functions, compounds generated in this project may serve as interesting candidates for the treatment of depressive disorders and addiction.  Moreover, KOR agonism produces antinociception and blocks itch and may also represent potential therapeutic avenues.

Additional efforts in the laboratory focus on evaluating how antipsychotic drugs and mood altering neurotransmitters such as serotonin act at serotonin receptors.  Recently, we have begun searching for biased agonism among cannabinoid receptor (CB1) agonists in collaboration with Dr. Alex Makriyannis at Northeastern University.  Given the emerging implications for using cannabinoids as therapeutics for a wide-range of disorders, there are many opportunities for new drug development. 

 

Education

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

Professional Experience

1999-2003 Post-doc/ Res. Asst. Prof.  Cell Biology, Duke University Medical Center, Durham, NC, Mentor: Marc G. Caron, Ph.D.

Awards & Professional Activities

Awards



  • The John J. Abel Award from the American Society of Pharmacology & Experimental Therapeutics and Pfizer (06/11).

  • The Joseph Cochin Young Investigator Award from the College on Problems of Drug Dependence 6/09

  • Featured as one of “30 in Their 30s” by BioOhio, “The Voice of Bioscience in Ohio” 5/07.

  • 2005 Committee on Women in Neuroscience Career Development Award, sponsored by the Society for Neuroscience and Merck 11/05.

  • School of Biomedical Sciences Award for Excellence in Research, The Ohio State University 9/06 2005

  • College on Problems of Drug Dependence Early Career Investigator Award 6/02

  • 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)


Activities



  • Faculty of 1000 Prime; Pain: Basic Research (2014-)

  • Editorial Board, Journal of Biological Chemistry (2013-2018)

  • Chair, Neuropharmacology Division, ASPET (2013-2015)

  • MiniReview editor, Molecular Pharmacology (2010-2013)

  • Chair, Scripps Florida Theme Committee for Graduate Education Self Evaluation (2012-)

  • NIH ZRG1 MDCN-Molecular Neuropharmacology and Signaling Study Section (MNPS) Member (2009-2013)

  • Vice-Chair of IACUC (TSRI, 2013-)

  • Co-Founder, Mencuro Therapeutics, Inc. 12/10


 


Organizer



  • Keystone Meeting “G Protein-Coupled Receptors: Structure, Signaling and Drug Discovery” (co-organizers: Arthur Christopoulos and Dominic Behan), February, 2016.

  • Lorentz Workshop  “Exploring the biology of GPCRs: bridging biochemistry, therapeutics and physiology.” (co-organizers: Paul Taghert, Michael Nitabach, Martin Lohse and Martine Smit). Leiden, The Netherlands, August 2014

  • 4th GPCR Colloquium (co-organizers: Graeme Milligan and Roger Sunahara) Following ASPET/Experimental Biology, April, 2013, in Boston, MA.


 

Selected References

All Publications

Schmid CL, Streicher, JM, Meltzer HY, Bohn, LM.  (2014).  Clozapine acts as an agonist at serotonin 2A receptors to counter MK-801- induced behaviors through a βarrestin2-independent activation of Akt.  Neuropsychopharmacology 39(8):1902-13 PMID: 24531562

Zhou L and Bohn LM. (2014) Functional Selectivity of GPCR Signaling in Animals.  Current Opinion in Cell Biology (special edition, M von Zastrow and J Benovic, Editors), 27:102-8. PMID: 24680435

Zhou L, Lovell KM, Frankowski KJ, Slauson SR, Phillips AM, Streicher JM, Stahl EL, Schmid CL, Hodder P, Madoux F, Cameron MD, Prisinzano TE, Aube J, Bohn LM. (2013) Development of functionally selective, small molecule agonists at kappa opioid receptors. J Biol Chem.  Nov 1. [Epub ahead of print]  PMID:24187130

Schmid CL, Streicher JM, Groer CE, Munro TA, Zhou L, Bohn LM. (2013) Functional Selectivity of 6'-guanidinonaltrindole (6'-GNTI) at Kappa Opioid Receptors in Striatal Neurons. J Biol Chem. 288, 22387-22398.  PMID:  23775075

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]

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]

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]

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]

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]

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] 

Fei G, Raehal K, Liu S, Qu MH, Sun X, Wang GD, Wang XY, Xia Y, Schmid CL, Bohn LM, Wood JD. Lubiprostone reverses the inhibitory action of morphine on intestinal secretion in guinea pig and mouse. J Pharmacol Exp Ther.2010 Jul; 334-40.doi:10.1124/jpet.110.166116. Epub 2010 Apr 20.
PMID: 20406855 [PubMed - indexed for MEDLINE]

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]

Raehal KM, Schmid CL, Medvedev IO, Gainetdinov RR, Premont RT, Bohn LM. Morphine-induced physiological and behavioral responses in mice lacking G protein-coupled receptor kinase 6. Drug Alcohol Depend.2009 Oct 1;104(3):187-96. doi: 10.1016/j.drugalcdep.2009.04.011. Epub 2009 Jun 3.
PMID: 19497686 [PubMed - indexed for MEDLINE]

Schmid CL, Bohn LM.  Physiological and pharmacological implications of beta-arrestin regulation. Pharmacol Ther. 2009 Mar; 121(3):285-93. doi: 10.1016/j.pharmthera.2008.11.005.Epub 2008 Dec 6.Review.
PMID 19100766 [PubMed - indexed for MEDLINE]

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.

Tidgewell K, Groer CE, Harding WW, Lozama A, Schmidt M, Marquam A, Hiemstra J, Partilla JS, Dersch CM, Rothman RB, Bohn LM, Prisinzano TE. Herkinorin analogues with differential beta-arrestin-2 interactions. J Med Chem.2008 Apr 24;51(8):2421-31. doi: 10.1021/jm701162g. Epub 2008 Apr 2.
PMID: 18380425 [PubMed - indexed for MEDLINE]

Schmid CL, Raehal KM, Bohn LM. 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. 2008 Jan 22;105(3):1079-84. doi: 10.1073/pnas.0708862105. Epub 2008 Jan 14.
PMID: 18195357 [PubMed - indexed for MEDLINE]

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

Bohn LM, Raehal KM. Opioid receptor signaling: relevance for gastrointestinal therapy. Curr Opin Pharmacol. 2006 Dec;
6(6):559-63. Epub 2006 Aug 28. Review.
PMID:16935560 [PubMed - indexing for MEDLINE]

Raehal KM, Bohn LM. Mu opioid receptor regulation and opiate responsiveness. AAPS J. 2005 Oct 19;7(3):E587-91. Review.
PMID: 16353937 [PubMed - indexed for MEDLINE]

Raehal KM, Walker JK, Bohn LM. Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther. 2005 Sep;314(3):1195-201. Epub 2005 Mar 18.
PMID: 15917400 [PubMed - indexed for MEDLINE]

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

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

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 Research Scientist Wins Prestigious John J. Abel Award in Pharmacology

Scientists Awarded $2.2 Million to Develop Treatment for Multi-Drug Addiction

Researchers Shed Light on How Serotonin Works

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

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?