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J. Biol. Chem., Vol. 278, Issue 2, 940-947, January 10, 2003
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T3-1 Anterior
Pituitary Cells*
,
From the Department of Pharmacology, State University of New York
Upstate Medical University, Syracuse, New York 13210-2339
In 
T3-1 mouse anterior pituitary gonadotropes,
chronic activation of gonadotropin-releasing hormone (GnRH) receptors
causes inositol 1,4,5-trisphosphate (InsP3) receptor
down-regulation (Willars, G. B., Royall, J. E., Nahorski,
S. R., El-Gehani, F., Everest, H. and McArdle, C. A. (2001)
J. Biol. Chem. 276, 3123-3129). In the current study,
we sought to define the mechanism behind this adaptive response. We
show that GnRH induces a rapid and dramatic increase in
InsP3 receptor polyubiquitination and that proteasome
inhibitors block InsP3 receptor down-regulation and cause
the accumulation of polyubiquitinated receptors. Thus, the ubiquitin/proteasome pathway is active in T3-1 cells, and GnRH regulates the levels of InsP3 receptors via this mechanism.
Given these findings and further characterization of this system, we also examined the possibility that T3-1 cells could be used to examine the ubiquitination of exogenous InsP3 receptors
introduced by cDNA transfection. This was found to be the case,
since exogenous wild-type InsP3 receptors, but not
binding-defective mutant receptors, were polyubiquitinated in a
GnRH-dependent manner, and agents that inhibited the
polyubiquitination of endogenous receptors also inhibited the
polyubiquitination of exogenous receptors. Further, we used this system
to determine whether phosphorylation was involved in triggering
InsP3 receptor polyubiquitination. This was not the case,
since mutation of serine residues 1588 and 1755 (the predominant
phosphorylation sites in the type I receptor) did not inhibit
polyubiquitination. In total, these data show that the
ubiquitin/proteasome pathway is active in anterior pituitary cells,
that this pathway targets both endogenous and exogenous
InsP3 receptors in GnRH-stimulated T3-1 cells, and that,
in contrast to the situation for many other substrates, phosphorylation
does not trigger InsP3 receptor polyubiquitination.
To whom correspondence should be addressed: Dept. of Pharmacology,
SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY
13210-2339. Tel.: 315-464-7956; Fax: 315-464-8014; E-mail: wojcikir@mail.upstate.edu.
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