Laura Bohn, Ph.D.
Faculty, Graduate Program
Ph.D., Biochemistry & Molecular Biology, St. Louis University School of Medicine, 1999
Department of Molecular Therapeutics
Department of Neuroscience
The Scripps Research Institute
130 Scripps Way 2A2
Jupiter, Florida 33458
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.
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.
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.
Raehal KM, Walker JK, Bohn LM. (2005). Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther. 314(3):1195-201.
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. 30(40):13513-24.
Tarselli MA, Raehal KM, Brasher AK, Streicher JM, Groer CE*, Cameron MD, Bohn LM and Micalizio GC. (2011). Synthesis of conolidine, a Potent Non-opioid Analgesic for Tonic and Persistent Pain. Nature Chemistry 3(6)::449-453.
Raehal KM, Schmid CL*, Groer CE*, Bohn LM. (2011). Functional selectivity at the mu opioid receptor: Implications for understanding opiate analgesia and tolerance. Pharmaco. Rev. 63(4):1001-19.
Schmid CL, Streicher JM, Groer CE, Munro TA, Zhou L, Bohn LM. (2013) Functional selectivity of 6'-guanidinonaltrindole (6'-GNTI) at κ-opioid receptors in striatal neurons. J Biol Chem. 288(31):22387-22398.
Zhou L, Lovell KM, Frankowski KJ, Slauson SR, Phillips AM, Streicher JM, Stahl E, Schmid CL, Hodder P, Madoux F, Cameron MD, Prisinzano TE, Aubé J, Bohn LM. (2013) Development of functionally selective, small molecule agonists at kappa opioid receptors. J Biol Chem. 288(51):36703-36716.
Raehal KM, Bohn LM. (2014) β-arrestins: regulatory role and therapeutic potential in opioid and cannabinoid receptor-mediated analgesia.Handb Exp Pharmacol. 219:427-443.
Zhou L, Bohn LM. (2014) Functional selectivity of GPCR signaling in animals. Curr Opin Cell Biol. 27:102-108.
Stahl EL, Zhou L, Ehlert FJ, Bohn LM. (2015) A novel method for analyzing extremely biased agonism at G protein-coupled receptors. Mol Pharmacol. 87(5): 866-877.
Luttrell LM, Maudsley S, Bohn LM. (2015) Fulfilling the Promise of "Biased" G Protein-Coupled Receptor Agonism. Mol Pharmacol. 88(3): 579-588.
Rankovic Z, Brust TF, Bohn LM. (2016) Biased agonism: An emerging paradigm in GPCR drug discovery. Bioorg Med Chem Lett. 26(2):241-250.
* Graduate Student authored publication.
** Undergraduate Trainee authored publication.
Awards, Recognition, Appointments, and Honors
2011 The John J. Abel Award from the American Society of Pharmacology & Experimental Therapeutics and Pfizer
2010-2011 MiniReview Editor for Molecular Pharmacology.
2010 Co-Founder, Director of Scientific Advisory Board, Mencuro Therapeutics, Inc.
2010 Roundtable Discussant and Speaker, Neuropharmacology Conference: High Resolution Neuropharmacology: Structure Changes the Paradigm.
2009-2013 NIH ZRG1 MDCN- Molecular Neuropharmacology and Signaling Study Section (MNPS) Member
2009 The Joseph Cochin Young Investigator Award from the College on Problems of Drug Dependence
2007 Featured as one of “30 in Their 30s” by BioOhio, “The Voice of Bioscience in Ohio”
2006 School of Biomedical Sciences Award for Excellence in Research, The Ohio State University
2005 Committee on Women in Neuroscience Career Development Award, sponsored by the Society for Neuroscience and Merck
2002 College on Problems of Drug Dependence Early Career Investigator Award
2002 Postdoctoral Research Award, Joint University of North Carolina - Chapel Hill and Duke University Cell and Developmental Biology Retreat
2000-02 Ruth L. Kirschstein National Research Service Award (NRSA) Postdoctoral Fellowship (NIDA F32)
1996-99 Ruth L. Kirschstein National Research Service Award (NRSA) Predoctoral Fellowship (NIDA F31)
1997-98 Student Representative to University Board of Governors
1997-98 President, Graduate Student Association
1996 Graduate Student Association Award for Research Excellence
1996-97 Vice President, Graduate Student Association
1993 Graduation: Cum Laude, Virginia Tech