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Truncation of the Thyrotropin-releasing Hormone Receptor Carboxyl Tail Causes Constitutive Activity and Leads to Impaired Responsiveness in Xenopus Oocytes and AtT20 Cells (*)

N. Matus-Leibovitch,D. Nussenzveig,M. Gershengorn,Y. Oron

Published 1995 in Journal of Biological Chemistry

ABSTRACT

We studied the activity of a truncated thyrotropin-releasing hormone receptor (TRH-R), which lacks the last 59 amino acids of the carboxyl tail, where Cys-335 was mutated to a stop codon (C335Stop) (Nussenzveig, D. R., Heinflink, M., and Gershengorn, M. C.(1993) J. Biol. Chem. 268, 2389-2392). In Xenopus laevis oocytes expressing C335Stop TRH-Rs, TRH binding was higher, whereas chloride current, Ca efflux, and [Ca] responses evoked by TRH were 23, 39, and 21%, respectively, of those in oocytes expressing wild type mouse pituitary TRH-Rs (WT TRH-Rs). In oocytes expressing C335Stop TRH-Rs, basal Ca efflux and [Ca] were twice those in oocytes expressing WT TRH-Rs; chelation of Ca caused a rapid increase in holding current, which is consistent with basal activation; and coexpression with other receptors caused inhibition of the responses to the other cognate agonists. In AtT20 pituitary cells stably expressing C335Stop TRH-Rs, thyrotropin-releasing hormone (TRH)-independent inositol phosphate formation was 1.32 ± 0.11-fold higher, basal [Ca] was 1.8 ± 0.2-fold higher, and the [Ca] response to TRH was much lower than in cells expressing WT TRH-Rs. We conclude that a TRH-R mutant truncated at Cys-335 exhibits constitutive activity that results in desensitization of the response to TRH.

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