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The Journal of Neuroscience, February 11, 2009, 29(6):1937-1946; doi:10.1523/JNEUROSCI.5343-08.2009

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 Previous Article

Behavioral/Systems/Cognitive
Role of p11 in Cellular and Behavioral Effects of 5-HT4 Receptor Stimulation

Jennifer L. Warner-Schmidt,1 Marc Flajolet,1 Abigail Maller,1 Emily Y. Chen,1 Hongshi Qi,2 Per Svenningsson,1,2 and Paul Greengard1

1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10065, and 2Center for Molecular Medicine, Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden

Correspondence should be addressed to Dr. Paul Greengard, 1230 York Avenue, Box No. 296, New York, NY 10065. Email: greengard{at}rockefeller.edu

p11 (S100A10), a member of a large family of S100 proteins, interacts with serotonin receptor 1B (5-HTR1B), modulates 5-HT1B receptor signal transduction, and is required for antidepressant responses to activation of this receptor. In the current study, we investigated the specificity of the interaction between 5-HTR1B and p11 by screening brain-expressed S100 proteins against serotonin and noradrenergic receptors. The data indicate that p11 is unique among its family members for its interactions with defined serotonin receptors. We identify a novel p11-interacting receptor (5-HTR4) and characterize the interaction between p11 and 5-HTR4, demonstrating that (1) p11 and 5-HTR4 mRNA and protein are coexpressed in brain regions that are relevant for major depression, (2) p11 increases 5-HTR4 surface expression and facilitates 5-HTR4 signaling, and (3) p11 is required for the behavioral antidepressant responses to 5-HTR4 stimulation in vivo. The essential role played by p11 in modulating signaling through 5-HT4 as well as 5-HT1B receptors supports the concept that this protein may be a key determinant of vulnerability to depression.

Key words: antidepressant; depression; RS67333; S100A10; serotonin receptor; agonist

Received Nov. 6, 2008; revised Jan. 6, 2009; accepted Jan. 12, 2009.

Correspondence should be addressed to Dr. Paul Greengard, 1230 York Avenue, Box No. 296, New York, NY 10065. Email: greengard{at}rockefeller.edu






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