Marc Caron

Overview:

Studies of the mechanisms of action and regulation of hormones and neurotransmitters at the cellular and molecular levels constitute the main goals our of research activities. G protein-coupled receptors (GPCR) mediate the actions of signaling molecules from unicellular organisms to man. We have used adrenergic and dopamine receptors to characterize the structure/function and regulation mechanisms of these prototypes of G protein-coupled receptors. Another approach has been to characterize the nature of neurotransmitter transporters for dopamine, serotonin and other neurotransmitters in an attempt to understand their function in normal and pathological neurotransmission. Another goal of our laboratory is to define the genes and pathways involved in the reinforcing properties of drugs of abuse using both forward and reverse genetic approaches. Our laboratory uses biochemical, molecular biology and gene targeting approaches to examine these questions.

Positions:

James B. Duke Distinguished Professor of Cell Biology

Cell Biology
School of Medicine

Professor of Cell Biology

Cell Biology
School of Medicine

Vice-Chair for Science and Research in the Department of Cell Biology

Cell Biology
School of Medicine

Professor in Neurobiology

Neurobiology
School of Medicine

Professor in Medicine

Medicine, Cardiology
School of Medicine

Faculty Network Member of the Duke Institute for Brain Sciences

Duke Institute for Brain Sciences
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

Ph.D. 1973

University of Miami

Grants:

Control of Excitatory Synapse Formation by Huntingtin

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Co-Mentor
Start Date
End Date

Mechanistic studies of Mas receptor activation and its role in aortic aneurysm formation

Administered By
Medicine, Cardiology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Exploiting Dopamine Receptor Functional Selectivity as an Approach to Treat Parkinson's Symptoms

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Leveraging Functional Selectivity in the Neurotensin Receptor 1-Mediated Treatment of Addiction

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Managing L-­DOPA Induced Dyskinesias by Targeting Dopamine D1 Receptor Biased Signaling

Awarded By
Michael J. Fox Foundation for Parkinson's Research
Role
Principal Investigator
Start Date
End Date

Publications:

HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase.

HER2-positive breast cancers are among the most heterogeneous breast cancer subtypes. The early amplification of HER2 and its known oncogenic isoforms provide a plausible mechanism in which distinct programs of tumor heterogeneity could be traced to the initial oncogenic event. Here a Cancer rainbow mouse simultaneously expressing fluorescently barcoded wildtype (WTHER2), exon-16 null (d16HER2), and N-terminally truncated (p95HER2) HER2 isoforms is used to trace tumorigenesis from initiation to invasion. Tumorigenesis was visualized using whole-gland fluorescent lineage tracing and single-cell molecular pathology. We demonstrate that within weeks of expression, morphologic aberrations were already present and unique to each HER2 isoform. Although WTHER2 cells were abundant throughout the mammary ducts, detectable lesions were exceptionally rare. In contrast, d16HER2 and p95HER2 induced rapid tumor development. d16HER2 incited homogenous and proliferative luminal-like lesions which infrequently progressed to invasive phenotypes whereas p95HER2 lesions were heterogenous and invasive at the smallest detectable stage. Distinct cancer trajectories were observed for d16HER2 and p95HER2 tumors as evidenced by oncogene-dependent changes in epithelial specification and the tumor microenvironment. These data provide direct experimental evidence that intratumor heterogeneity programs begin very early and well in advance of screen or clinically detectable breast cancer. IMPLICATIONS: Although all HER2 breast cancers are treated equally, we show a mechanism by which clinically undetected HER2 isoforms program heterogenous cancer phenotypes through biased epithelial specification and adaptations within the tumor microenvironment.
Authors
Ginzel, JD; Acharya, CR; Lubkov, V; Mori, H; Boone, PG; Rochelle, LK; Roberts, WL; Everitt, JI; Hartman, ZC; Crosby, EJ; Barak, LS; Caron, MG; Chen, JQ; Hubbard, NE; Cardiff, RD; Borowsky, AD; Lyerly, HK; Snyder, JC
MLA Citation
Ginzel, Joshua D., et al. “HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase.Mol Cancer Res, vol. 19, no. 10, Oct. 2021, pp. 1699–711. Pubmed, doi:10.1158/1541-7786.MCR-21-0215.
URI
https://scholars.duke.edu/individual/pub1485787
PMID
34131071
Source
pubmed
Published In
Mol Cancer Res
Volume
19
Published Date
Start Page
1699
End Page
1711
DOI
10.1158/1541-7786.MCR-21-0215

Addition to "Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity".

Authors
Martini, ML; Ray, C; Yu, X; Liu, J; Pogorelov, VM; Wetsel, WC; Huang, X-P; McCorvy, JD; Caron, MG; Jin, J
MLA Citation
Martini, Michael L., et al. “Addition to "Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity".Acs Chem Neurosci, vol. 12, no. 8, Apr. 2021, p. 1464. Pubmed, doi:10.1021/acschemneuro.1c00186.
URI
https://scholars.duke.edu/individual/pub1478349
PMID
33830725
Source
pubmed
Published In
Acs Chemical Neuroscience
Volume
12
Published Date
Start Page
1464
DOI
10.1021/acschemneuro.1c00186

Biased Coupling to β-Arrestin of Two Common Variants of the CB2 Cannabinoid Receptor.

β-arrestins are partners of the G protein-coupled receptors (GPCRs), regulating their intracellular trafficking and signaling. Development of biased GPCR agonists, selectively targeting either G protein or β-arrestin pathways, are in the focus of interest due to their therapeutic potential in different pathological conditions. The CB2 cannabinoid receptor (CB2R) is a GPCR involved in various functions in the periphery and the central nervous system. Two common occurring variants of CB2R, harboring Q63R or L133I missense mutations, have been implicated in the development of a diverse set of disorders. To evaluate the effect of these mutations, we characterized the binding profile of these mutant CB2 receptors to G proteins and β-arrestin2. Although their ability to inhibit cAMP signaling was similar, the Q63R mutant had increased, whereas the L133I mutant receptor had decreased β-arrestin2 binding. In line with these observations, the variants also had altered intracellular trafficking. Our results show that two common variants of the CB2 receptor have biased signaling properties, which may contribute to the pathogenesis of the associated disorders and may offer CB2R as a target for further development of biased receptor activation strategies.
Authors
Turu, G; Soltész-Katona, E; Tóth, AD; Juhász, C; Cserző, M; Misák, Á; Balla, A; Caron, MG; Hunyady, L
MLA Citation
Turu, Gábor, et al. “Biased Coupling to β-Arrestin of Two Common Variants of the CB2 Cannabinoid Receptor.Front Endocrinol (Lausanne), vol. 12, 2021, p. 714561. Pubmed, doi:10.3389/fendo.2021.714561.
URI
https://scholars.duke.edu/individual/pub1496450
PMID
34484125
Source
pubmed
Published In
Frontiers in Endocrinology
Volume
12
Published Date
Start Page
714561
DOI
10.3389/fendo.2021.714561

Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery.

G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in the genome and the most successful family of targets of FDA-approved drugs. New frontiers in GPCR drug discovery remain, however, as achieving receptor subtype selectivity and controlling off- and on-target side effects are not always possible with classic agonist and antagonist ligands. These challenges may be overcome by focusing development efforts on allosteric ligands that confer signaling bias. Biased allosteric modulators (BAMs) are an emerging class of GPCR ligands that engage less well-conserved regulatory motifs outside the orthosteric pocket and exert pathway-specific effects on receptor signaling. The unique ways that BAMs texturize receptor signaling present opportunities to fine-tune physiology and develop safer, more selective therapeutics. Here, we provide a conceptual framework for understanding the pharmacology of BAMs, explore their therapeutic potential, and discuss strategies for their discovery.
Authors
Slosky, LM; Caron, MG; Barak, LS
MLA Citation
Slosky, Lauren M., et al. “Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery.Trends Pharmacol Sci, vol. 42, no. 4, Apr. 2021, pp. 283–99. Pubmed, doi:10.1016/j.tips.2020.12.005.
URI
https://scholars.duke.edu/individual/pub1474564
PMID
33581873
Source
pubmed
Published In
Trends Pharmacol Sci
Volume
42
Published Date
Start Page
283
End Page
299
DOI
10.1016/j.tips.2020.12.005

Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors.

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins. G protein-mediated signaling and β-arrestin-mediated signaling have been considered separable. We show here that GPCRs promote a direct interaction between Gαi protein subtype family members and β-arrestins regardless of their canonical Gα protein subtype coupling. Gαi:β-arrestin complexes bound extracellular signal-regulated kinase (ERK), and their disruption impaired both ERK activation and cell migration, which is consistent with β-arrestins requiring a functional interaction with Gαi for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of Gαi:β-arrestin signaling complexes.
Authors
Smith, JS; Pack, TF; Inoue, A; Lee, C; Zheng, K; Choi, I; Eiger, DS; Warman, A; Xiong, X; Ma, Z; Viswanathan, G; Levitan, IM; Rochelle, LK; Staus, DP; Snyder, JC; Kahsai, AW; Caron, MG; Rajagopal, S
MLA Citation
Smith, Jeffrey S., et al. “Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors.Science, vol. 371, no. 6534, Mar. 2021. Pubmed, doi:10.1126/science.aay1833.
URI
https://scholars.duke.edu/individual/pub1472830
PMID
33479120
Source
pubmed
Published In
Science
Volume
371
Published Date
DOI
10.1126/science.aay1833