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Molecular Medicine

Faculty

Laura M. Bohn, Ph.D.

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

Scripps Research Joint Appointments

Professor, Department of Neuroscience
Faculty, Graduate Program

Other Joint Appointments

Florida Atlantic University Brain Institute

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.

Recently, we have begun evaluating ligands for biased agonism among cannabinoid receptor (CB1 and CB2) 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. This collaboration has also involved working with Dr. Ray Stevens (USC) and Dr. James Liu (Shanghai Tech) to solve the first crystal structures of antagonist and agonist bound CB1 receptors. Additional efforts in the laboratory focus on evaluating how antipsychotic drugs and mood altering neurotransmitters such as serotonin act at serotonin receptors.  

Since the receptors described above are involved in modulating mood, motivation, and sensory perception, it stands to reason that our laboratory is most interested in developing means to treat pain, whether due to injury, disease or mental state, in a manner that adequately manages the pain, without causing deabilitating side effects.

 

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

1993  B.A. Chemistry (research mentor: Neil Castignoli, Jr., Ph.D.) and B.S. Biochemistry (research mentor: David Bevan, Ph.D.), Virginia Tech.
1999  Ph.D. Biochemistry & Molecular Biology, St. Louis University School of Medicine, Mentor: Carmine J. Coscia, Ph.D.
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



  • Gordon Research Conference on Molecular Pharmacology (elected with co-chair: Roger Sunahara), TBD, 2019.

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

  • ASPET program committee member. 2015-2017.

  • 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

Hua T, Vemuri K, Nikas SP, Laprairie RB, Wu Y, Pu M,  Qu L, Korde A, Jiang S,  Ho J-H,  Han GW, Ding K, Li S, Liu H, Hanson MA, Zhao S*, Bohn LM*, Makriyannis A*, Stevens RC, Liu J-Z*. (2017) Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature.  July 6, 2017 in press.   *corresponding

Bohn LM and Aubé J. (2017) Seeking (and Finding) Biased Ligands of the Kappa Opioid Receptor ACS Med. Chem. Lett.  8 (7): 694–700

Mason JW, Schmid CL, Bohn LM, Roush WR. (2017) Stolonidiol: Synthesis, Target Identification, and Mechanism for Choline Acetyltransferase Activation. J Am Chem Soc. 139(16):5865-9. PMID: 28414442

Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y,  Zhao S, Shui W, Li S, Korde A, Laprairie RB, Stahl EL, Ho J-H, Zvonok N, Zhou H, Kufareva I, Wu B, Zhao Q, Hanson MA, Bohn LM*, Makriyannis A*, Stevens RC*, Liu J-Z.* (2016). Crystal Structure of the Human Cannabinoid Receptor CB1. Cell164: 750-762. PMID: 27768894. *corresponding.

Brust TF, Morgenweck J, Kim SA, Rose JH, Locke J, Schmid CL, Zhou L, Stahl EL, Cameron MD, Scarry SM, Aubé J, Jones SL, Martin TJ, Bohn LM. (2016) Biased agonists of the kappa opioid receptor suppress pain and itch while not causing sedation or dysphoria. Sci. Signal.  9: (456)ra117. PMID: 27899527

Rankovic Z, Brust TF, Bohn LM. (2016) Biased Agonism: An emerging paradigm in GPCR drug discovery.  Bioorg. & Med. Chem. 26(2):241-50 PMID: 26707396

Morgenweck J, Frankowski KJ, Prisinzano TE, Aubé J, Bohn LM, (2015) Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus. Neuropharm. 99: 600-609  PMID: 26318102

Luttrell LM, Maudsley S, Bohn LM. (2015) Fulfilling the Promise of 'Biased' GPCR Agonism. Mol Pharmacol. 88(3):579-88  PMID: 26134495

Bohn LM, Lohse MJ, Nitabach M, Taghert PH, Smit MJ. (2015) Exploring the Biology of GPCRs from In Vitro to In Vivo. Mol Pharmacol. 88(3):534-5 Invited Commentary. PMID: 26162863.  Special Edition of the Journal- Organizers’ commentary.

Stahl EL, Zhou L, Ehlert FJ, Bohn LM (2015) A novel method for analyzing extremely biased agonism at G protein-coupled receptors. Mol Pharm 87: 866-77 PMID: 25680753

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

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]

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]

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, CL 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, 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]

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.

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, 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

America’s Long-Overdue Opioid Revolution Is Finally Here - The Smithsonian Magazine

Biased for benefit: Stimulating the world's most popular drug targets with more nuance- Nature Medicine

Palm Beach County scientists: Promising addiction treatment discovery - Palm Beach Post

Compound Offers Pain Relief without the Complications - Scientific American

The search for a painkiller that works without danger of addiction - The Washington Post

Scientists Engineer An Opioid That May Reduce Pain With Less Risk - NPR Morning Edition

New opioids could relieve pain without dangerous side effects - CNBC

Novel compound to alleviate pain and itch discovered - Science Daily

Kratom Drug Ban May Cripple Promising Painkiller Research - Scientific American

If DEA blocks kratom, promising research on opioid alternative may suffer- PBS News Hour

Medicinal Chemistry: New lead for pain treatment - Nature News

Natural Pain-Killing Chemical Synthesized: Making conolidine in the lab could further drug research - US News & World Report

Molecular Medicine Seminar Series

CA Faculty

Asahara, Hiroshi
Balch, William E.
Boddy, Michael
Buxbaum, Joel
Catz, Sergio
Conti, Bruno
Cravatt, Benjamin
D'Lima, Darryl
DerMardirossian, Celine
Deryugina, Elena
Elias, Darlene
Encalada, Sandra
Felding, Brunhilde
Fowler, Velia
Friedlander, Martin
Gerace, Larry
Gottesfeld, Joel
Griffin, John
Hanneken, Anne
Heeb, Mary Jo
Henderson, Scott
Hoch, James
Joazeiro, Claudio
Johnson, Eric
Kanaji, Taisuke
Kay, Steve
Kelly, Jeffery
Koziol, James
Lamia, Katja
Lazzerini Denchi, Eros
Lipton, Stuart
Loring, Jeanne F.
Loskutoff, David
Lotz, Martin
Makarenkova, Helen P.
Mc Millan, Robert
Miles, Lindsey
Milner, Richard
Modena, Brian
Mosnier, Laurent
Paulson, James C.
Perego, Marta
Petrascheck, Michael
Pollard, Kenneth Michael
Quigley, James P.
Reed, Steven
Roberts, Edward
Rosen, Hugh
Ruggeri, Zaverio
Russell, Paul
Saez, Enrique
Smider, Vaughn
Srinivasan, Supriya
Steinhubl, Steven
Sutcliffe, J.
Tan, Eng
Topol, Eric
Vanderklish, Peter
Vogt, Peter K.
Waalen, Jill
Wiseman, Luke
Wittenberg, Curt
Wolan, Dennis W.
Wu, Peng
Wu, Xiaohua
Yang, Xiang-Lei
Yates III, John


FL Faculty

Bohn, Laura M.
Cameron, Michael
Duckett, Derek
Gill, Matt
Griffin, Patrick
Hansen, Scott
Kamenecka, Theodore
Kissil, Joseph
Luo, Junli
McDonald, Patricia
Miller, Courtney
Niedernhofer, Laura
Phinney, Donald G.
Robbins, Paul
Scampavia, Louis
Schimmel, Paul
Smith, Roy
Spicer, Timothy


Affiliated Faculty

Cline, Hollis
Kojetin, Douglas
Lairson, Luke
Paegel, Brian
Rumbaugh, Gavin
Shen, Ben
Solt, Laura A
Su, Andrew
Wu, Chunlei


Adjunct Faculty