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Originally published In Press as doi:10.1074/jbc.M414587200 on January 31, 2005

J. Biol. Chem., Vol. 280, Issue 17, 16851-16860, April 29, 2005
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A Novel Pineal-specific Product of the Oligopeptide Transporter PepT1 Gene

CIRCADIAN EXPRESSION MEDIATED BY cAMP ACTIVATION OF AN INTRONIC PROMOTER*{boxs}

Pascaline Gaildrat{ddagger}, Morten Møller§, Sujira Mukda§||, Ann Humphries**{ddagger}{ddagger}, David A. Carter**, Vadivel Ganapathy§§, and David C. Klein{ddagger}¶¶

From the {ddagger}Section on Neuroendocrinology, Laboratory of Developmental Neurobiology, NICHD, National Institutes of Health, Bethesda, Maryland 20892-4480, the §Institute of Medical Anatomy, Panum Institute, University of Copenhagen, Copenhagen DK-2200, Denmark, the Neuro-Behavioural Biology Center, Institute of Science and Technology for Research and Development, Mahidol University, Salaya Campus, Nakornpathom 73170, Thailand, the **School of Biosciences, Cardiff University, Cardiff CF103US, United Kingdom, and the §§Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912

The oligopeptide transporter 1, PepT1, is a member of the Slc15 family of 12 membrane-spanning domain transporters; PepT1 has proton/peptide cotransport activity and is selectively expressed in intestinal epithelial cells, where it is responsible for the nutritional absorption of di- and tri-peptides. Here, a novel PepT1 gene product has been identified in the rat pineal gland, termed pgPepT1. It encodes a 150-amino acid protein encompassing the C-terminal 3 membrane-spanning domains of intestinal PepT1 protein, with 3 additional N-terminal residues. Expression of pgPepT1 appears to be restricted to the pineal gland and follows a marked circadian pattern with >100-fold higher levels of mRNA occurring at night; this is accompanied by an accumulation of membrane-associated pgPepT1 protein (~16 kDa). The daily rhythm in pgPepT1 mRNA is regulated by the well described neural pathway that controls pineal melatonin production. This includes the retina, the circadian clock in the suprachiasmatic nucleus, central structures, and projections from the superior cervical ganglia; activation of this pathway results in the release of norepinephrine. Here it was found that pgPepT1 expression is mediated by a norepinephrine -> cyclic AMP mechanism that activates an alternative promoter located in intron 20 of the gene. pgPepT1 protein was found to have transporter-modulator activity; it could contribute to circadian changes in pineal function through this mechanism.


Received for publication, December 27, 2004

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{boxs} The on-line version of this article (available at http//www.jbc.org) contains Supplemental Fig. S1.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY860424.

|| Supported by a Royal Golden Jubilee Ph.D. Grant from the Thailand Research Fund and Danish Medical Research Council (Grant J nr. 22-02-0288).

{ddagger}{ddagger} Supported by the Wellcome Trust.

¶¶ To whom correspondence should be addressed: National Institutes of Health, Bldg. 49, Rm. 6A-82, Bethesda, MD 20892-4480. Tel.: 301-496-6914; Fax: 301-480-3526; E-mail: klein{at}helix.nih.gov.


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