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J. Biol. Chem., Vol. 283, Issue 17, 11485-11492, April 25, 2008

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A Carboxyl-terminal Sequence in the Lutropin β Subunit Contributes to the Sorting of Lutropin to the Regulated Pathway^*

From the Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

Although synthesized in the same pituitary gonadotropes, the secretion profiles of lutropin (LH) and follitropin (FSH) differ. LH is secreted through a regulated pathway and associated with a bolus release at mid-estrous cycle. In contrast, the majority of FSH is secreted constitutively with an incremental increase until ovulation. Both share an identical subunit, and thus theβ subunit contains determinants for sorting into the regulated pathway. Previously, we demonstrated that a hydrophobic carboxyl-terminal heptapeptide of the LHβ subunit (Leu-Ser-Gly-Leu-Leu-Phe-Leu), not found in the FSHβ subunit, influences the intracellular behavior of the LH dimer. To test the hypothesis that the peptide contributes to differential sorting, we monitored the fates of LH and LHT (LHβ subunit lacking the carboxyl-terminal seven amino acids) dimers in the rat somatotrope-derived GH₃ cell line in which both the regulated and constitutive secretory pathways operate. Pulse-chase labeling demonstrated that the LHT dimer was diverted to the constitutive pathway, resulting in a significant decrease in the corresponding intracellular pool. Forskolin stimulated LH dimer release 3-fold, which was accompanied by a parallel decrease of intracellular LH; only marginal forskolin stimulation of LHT was seen. Immunofluorescence after cycloheximide treatment demonstrated decreased retention of LHT compared with LH, consistent with increased constitutive secretion of LHT. We also demonstrated that fusing the heptapeptide to the carboxyl terminus of the FSHβ subunit resulted in an increased regulated secretion of this FSH analog compared with wild-type FSH. These data are the first to identify a novel structural determinant responsible for the sorting of a member of the glycoprotein hormone family into the regulated secretory pathway.

Received for publication, January 24, 2008 , and in revised form, February 20, 2008.

^* This manuscript was supported in part by National Institutes of Health (NIH) Grant DR065155, NIH Neuroscience Blueprint Core Grant NS057105 to Washington University, and the Bakewell Family Foundation. 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.

¹ Both authors contributed equally to this manuscript.

² Supported by Training Grant T32HD049305-03 from the National Institutes of Health/NICHD.

³ To whom correspondence should be addressed: 660 S. Euclid Ave., Box 8103, St. Louis, MO 63110. Tel.: 314-362-2556; Fax: 314-362-7051; E-mail: iboime{at}wustl.edu.

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