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Marc Caron

James B. Duke Professor
Cell Biology
Research Interest: 
Membranes and organelles
Signal transduction
Research Summary: 
Molecular and cellular mechanisms by which G protein-coupled receptors control normal and abnormal physiological functions.
Research Description: 

Our laboratory has worked in two main areas, the largest class of receptors in the genome, the G protein-coupled receptors (GPCR) and the family of neurotransmitter transporters. We have used biochemical, pharmacological, molecular biological and genetic approaches to elucidate some of the molecular and cellular mechanisms by which these receptors transmit and attenuate their signals and how transporters maintain the homeostatic control of neurotransmitters in the brain and affect behavior in the animal. In addition, to investigating these questions we have developed a series of mouse models with gain- and loss-of function mutations in the various components of these signaling systems. Our two main research endeavors are centered on the neurobiology of the dopamine and serotonin systems in the brain and how they control not only behavioral outcomes but also the molecular signaling mechanisms that underlie various deficits in these pathways that recapitulate disease conditions. Several years ago we provided the initial evidence indicating that GPCRs might be able to engage non-conventional signaling through components of the desensitization system. In our investigation of the brain dopamine system in some of our mouse models, we discovered that the dopamine D2 receptor exerted some of its physiological effects through a β-arrestin-dependent modulation of the Akt/GSK3 signaling pathway. We are using genetic approaches to understand the potential physiological importance of this mode of signaling in relation to schizophrenia-like phenotypes and responses to antipsychotics and psychostimulants in animal models. In our investigation of the serotonin system, we have developed a mouse model of serotonin deficiency that recapitulates a human mutation found in depressed patients. We are using such approaches to understand the contribution of this deficit as well as the mutational load in several key serotonin related genes to the etiology and susceptibility of an organism to develop depressive-like manifestations. Therefore, our approaches concern not only psychotic and mood disorders but also relate to the mechanisms by which drugs of abuse exert their actions. Over the past 20 years our laboratory has developed a number of animal models and reagents to probe the signaling mechanisms relevant to CNS disorders

Akt/GSK3 signaling in the action of psychotropic drugs.
Beaulieu JM, Gainetdinov RR, Caron MG.
Annu Rev Pharmacol Toxicol. 2009. 49:327-47.

Smoothened signaling in vertebrates is facilitated by a G protein-coupled receptor kinase.
Philipp M, Fralish GB, Meloni AR, Chen W, MacInnes AW, Barak LS, Caron MG.
Mol Biol Cell. 2008. 19:5478-89.

Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter.
Salahpour A, Ramsey AJ, Medvedev IO, Kile B, Sotnikova TD, Holmstrand E, Ghisi V, Nicholls PJ, Wong L, Murphy K, Sesack SR, Wightman RM, Gainetdinov RR, Caron MG.
Proc Natl Acad Sci U S A. 2008. 105:4405-10.

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner.
Ramsey AJ, Milenkovic M, Oliveira AF, Escobedo-Lozoya Y, Seshadri S, Salahpour A, Sawa A, Yasuda R, Caron MG.
Proc Natl Acad Sci U S A. 2011. 108:5795-800.

Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice.
Jacobsen JP, Siesser WB, Sachs BD, Peterson S, Cools MJ, Setola V, Folgering JH, Flik G, Caron MG.
Mol Psychiatry. 2012. 17:694-704.