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Duke Medical Center
Marc G. Caron, Ph.D.

(Biochemistry, University of Miami)

James B. Duke Professor,
Department of Cell Biology
Investigator, Howard Hughes
Medical Institute
Programs: CMB, Cancer Biology 		   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. Our laboratory uses biochemical, molecular biology and gene targeting approaches to examine these questions.




NEW  Powerpoint saved as Quicktime movie- A Novel Parkinsonian Model: Dopamine Depleted DAT Knockout Mice -MOV- large file (29MB)
Email m.caron@cellbio.duke.edu

487 CARL Building, Box 3287
Duke University Medical Center
Durham, NC 27710

Telephone
919-684-5433 (office)
919-684-6606/6094 (lab)
Fax 919-681-8641

Selected Publications

Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG. Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science. (2004),305(5681):217.
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Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG. Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci. (2004), 27:107-144. -PDF-

Quan H, Athirakul K, Wetsel WC, Torres GE, Stevens R, Chen YT, Coffman TM, Caron MG. Hypertension and impaired glycine handling in mice lacking the orphan transporter XT2. Mol Cell Biol. (2004), 24(10):4166-73.

Beaulieu JM, Sotnikova TD, Yao WD, Kockeritz L, Woodgett JR, Gainetdinov RR,
Caron MG. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci U S A. (2004), 101(14):5099-104.

Bohn LM, Gainetdinov RR, Caron MG. G protein-coupled receptor kinase/beta-arrestin systems and drugs of abuse: psychostimulant and opiate studies in knockout mice. Neuromolecular Med. (2004), 5(1):41-50.

Yao WD, Gainetdinov RR, Arbuckle MI, Sotnikova TD, Cyr M, Beaulieu JM,
Torres GE, Grant SG, Caron MG. Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron. (2004), 41(4):625-38.

Marion S, Weiner DM, Caron MG. RNA editing induces variation in desensitization and trafficking of 5-hydroxytryptamine 2c receptor isoforms. J Biol Chem. (2004), 279(4):2945-54.

Ferguson SS, Caron MG. Green fluorescent protein-tagged beta-arrestin translocation as a measure of G protein-coupled receptor activation. Methods Mol Biol.(2004), 237:121-6.

Barak LS, Wilbanks AM, Caron MG. Constitutive desensitization: a new paradigm for G protein-coupled receptor regulation. Assay Drug Dev Technol. (2003), 1(2):339-46.

Cyr M, Beaulieu JM, Laakso A, Sotnikova TD, Yao WD, Bohn LM, Gainetdinov RR, Caron MG. Sustained elevation of extracellular dopamine causes motor dysfunction and selective degeneration of striatal GABAergic neurons. Proc Natl Acad Sci U S A. (2003), 100(19):11035-40.

Gainetdinov RR, Bohn LM, Sotnikova TD, Cyr M, Laakso A, Macrae AD, Torres GE, Kim KM, Lefkowitz RJ, Caron MG, Premont RT. Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice. Neuron. (2003), 38(2):291-303.

Torres GE, Gainetdinov RR, Caron MG. Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci. (2003),(1):13-25.

Torres GE, Carneiro A, Seamans K, Fiorentini C, Sweeney A, Yao WD, Caron MG. Oligomerization and trafficking of the human dopamine transporter. Mutational analysis identifies critical domains important for the functional expression of the transporter. J Biol Chem. (2003), 278(4):2731-9.

Gainetdinov RR, Caron MG. Monoamine transporters: from genes to behavior. Annu Rev Pharmacol Toxicol. (2003), 43:261-84.
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Bohn LM, Lefkowitz RJ, Caron MG. Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice. J Neurosci. (2002), 22(23):10494-500.

Laakso A, Mohn AR, Gainetdinov RR, Caron MG. Experimental genetic approaches to addiction. Neuron. (2002), 36(2):213-28.

Gainetdinov RR, Sotnikova TD, Caron MG. Monoamine transporter pharmacology and mutant mice. Trends Pharmacol Sci. (2002), (8):367-73.

Wilbanks AM, Laporte SA, Bohn LM, Barak LS, Caron MG. Apparent loss-of-function mutant GPCRs revealed as constitutively desensitized receptors. Biochemistry. (2002), 41(40):11981-9.

Laporte SA, Miller WE, Kim KM, Caron MG. beta-Arrestin/AP-2 interaction in G protein-coupled receptor internalization: identification of a beta-arrestin binging site in beta 2-adaptin. J Biol Chem. (2002), 277(11):9247-54.

Barak, L.S., Oakley, R.H., Laporte, S.A. and Caron, M.G.(2001) Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus.PNAS 98:93-98.

Oakley, R.H., Laporte, S.A., Holt, J.A., Barak, L.S. and Caron, M.G. Molecular determinants underlying the formation of stable intracellular GPCR/complexes following receptor endocytosis. J. Biol. Chem. (2001) in press.

Torres, G.E., Yao, W.D., Mohn, A.R., Quan, H., Kim, K-M., Levey, A.I., Staudinger, J., and Caron, M.G. Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1. Neuron (2001) 30:121-134.

Laporte S.A., Oakley R.H., Holt J.A., Barak L.S., Caron M.G. (2000) The interaction of barrestin with the AP-2 adaptor is required for the clustering of b2-adrenergic receptor into clathrin-coated pits. J. Biol. Chem. 275: 23120-23126

Oakley R.H., Laporte S.A., Holt J.A., Caron M.G., Barak L.S., (2000) Differential affinities of visual arrestin, barrestin1, and barrestin2 for GPCRs delineate two major classes of receptors. J. Biol.Chem. 275: 17201-17210.

Bohn, L.M., Gainetdinov, R.R., Lin, F-T., Lefkowitz, R.J. and Caron, M.G. (2000) Mu-opioid receptor desensitization by beta-arrestin-2 determines morphin tolerance but not dependence.Nature (2000)408:(6813):720-3.

Bohn, L.M., Xu F., Gainetdinov R.R., and Caron, M.G.(2000) Potentiated Opioid Analgesia in Norepinephrine Transporter Knock-Out Mice. J. Neurosci. 24: 9040-9045.

Gainetdinov, R.R., Wetsel, W.C., Jones, S.R., Levin, E.D., Jaber, M. and Caron, M.G. (1999) Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283:397-401.

Laporte, S.A., Oakley, R.H., Zhang, J., Ferguson, S.G., Caron, M.G. and Barak, L.S. (1999) The b2-adrenergic receptor/barrestin complex recruits the clathrin adaptor AP-2 during endocytosis. Proc. Natl. Acad. Sci. 96:3712-3717.

Jones, S.R., Gainetdinov, R.R., Hu, X.-T., Cooper, D.C., Wightman, R.M., White, F.J. and Caron, M.G. (1999) Loss of autoreceptor functions in mice lacking the dopamine transporter. Nature Neuroscience 2:649-655.

Jones, S.R., Gainetdinov, R.R., Hu, X.-T., Cooper, D.C., Wightman, R.M., White, F.J. and Caron, M.G. (1999) Loss of autoreceptor functions in mice lacking the dopamine transporter. Nature Neuroscience 2:649-655.

Gainetdinov, R.R., Bohn, L.M., Walker, J.K.L., Laporte, S.A., Macrae, A.D., Caron, M.G., Lefkowitz, R.J. and Premont, R.T. (1999) Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice. Neuron, 24:1029-1036

Oakley, R.H., Laporte, S.A., Holt, J.A., Barak, L.S. and Caron, M.G. (1999) Association of barrestin with GPCRs during clathrin-mediated endocytosis dictates the profile of receptor resensitization. J. Biol. Chem., 274: 32248-32257

Bohn, L.M., Lefkowitz, R.J., Gainetdinov, R.R., Peppel, K., Caron, M.G. and Lin, F.-T. (1999) Enhanced morphine analgesia in mice lacking barrestin-2. Science, 286: 2495-2498

Xu, F., Wang, Y.-M., Wetsel, W.C., Jones, S.R., Miller, G.W. Gainetdinov, R.R. and Caron, M.G. (1999) Antidepressant-like behavior and hyper-responsiveness to cocaine in mice lacking the noradrenaline transporter. Nature Neuroscience, in press.

Zhang, J., Ferguson, S.S.G., Barak, L.S., Bodduluri, S.R., Laporte, S.A., Law, P.-Y. and Caron, M.G. (1998) Role for G protein-coupled receptor kinase in agonist-specific regulation of d-opioid receptor responsiveness. Proc. Natl. Acad. Sci. USA 95:7157-7162.

Barak, L.S., Ferguson, S.S.G., Zhang, J., Martenson, C., Meyer, T. and Caron, M.G. (1997) Internal trafficking and surface mobility of a functionally intact b2 adrenergic receptor-green fluorescent protein conjugate. Molec. Pharmacol. 51:177-184.

Bosse, R., Fumagalli, F., Jaber, M., Giros, B., Gainetdinov, R.R., Missale, C. and Caron, M.G. (1997) Anterior pituitary hypoplasia and dwarfism in mice lacking the dopamine transporter. Neuron 19:127-138.

Barak, L.S., Ferguson, S.S.G., Zhang, J. and Caron, M.G. (1997) A b-arrestin/green fluorescent protein biosensor for detecting G protein-coupled receptor activation. J .Biol .Chem. 272:27497-27500.

Wang, Y.-M., Gainetdinov, R.R., Fumagalli, F., Xu, F., Jones, S.R., Bock, C.B., Miller, G.W., Wightman, R.M. and Caron, M.G. (1997) Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19:1285-1296.

Jones, S.R., Gainetdinov, R.R., Jaber, M., Giros, B., Wightman, R.M. and Caron, M.G. (1997) Profound neuronal plasticity in response to inactivation of the dopamine transporter. PNAS 95:4029-4034.

Ferguson, S. S. G., Downey, W. E., III, Colapietro, A-M., Barak, L. S., Menard, L. and Caron, M. G. (1996) Role of b-arrestin in mediating agonist-promoted G protein-coupled receptor internalization. Science 271:363-366.

Giros, B., Jaber, M., Jones, S. R., Wightman, R. M. and Caron, M. G. (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606-612.

Ferguson, S. S. G., Mend, L., Barak, L. S., Koch, W. J., Colapietro, A.-M. and Caron, M. G. (1995) Role of phosphorylation in agonist-promoted b2-adrenergic receptor sequestration: Rescue of a sequestration-defective mutant receptor by bARK1. J. Biol. Chem. 270:24782-24789.









 Current Projects
L. Barak (asst. research professor): Mechanisms of GPCR.

L. Bohn (postdoc): Role of GPCR regulating mechanisms in pain perception.

M. Cyr (postdoc): GPCR regulatory mechanisms in dopaminergic neurotransmission.

R. Gainetdinov (assist. res. prof.): Characterization of dopamine CNS function in transporter knockout animals.

K-M. Kim (sabb. prof.): Cellular trafficking of dopamine receptors.

S. Laporte (postdoc): Role of arrestins in the desensitization and resensitization of GPCRs.

A. Mohn (postdoc): Modulation of dopaminergic CNS function by glutamate.

H. Quan (grad student): Characterization of orphan neurotransmitter transporters.

M. Shetzline (fellow): Desensitization of the VIP/secretin/parathyroid hormone receptor family.

G. Torres (postdoc): Cellular interaction and trafficking of neurotransmitter transporters.

J. Chien (3rd yr. MS): Role of phosphorylation in the interactions of AP2 and arrestins.

W-D. Yao (postdoc): GPCR regulatory mechanisms and neuronal activity.

A. Wilbanks (grad student): Biology of constitutively desensitized GPCRs.

K. Seamons (grad student): Structure and function of dopamine transporter.

A. Marin (foreign grad student): Functional characterization of Neurotransmitter transporter interacting proteins.

A. Laakson (postdoc): Interactions between dopamine and glutamate pathways in the brain.

T. Sotnikova (postdoc): Regulation of neurotransmitter homeostasis in the brain.}

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