Parallel regulation of membrane trafficking and dominant-negative effects by misrouted gonadotropin-releasing hormone receptor mutants

Paul E. Knollman, Jo Ann Janovick, Shaun P Brothers, P. Michael Conn

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Gonadotropin-releasing hormone (GnRH) receptor mutants from patients with hypogonadotropic hypogonadism are frequently misrouted proteins that exert a dominant-negative (DN) effect on human (h) wild-type (WT) receptor, due to oligomerization and retention in the endoplasmic reticulum. Pharmacologic chaperones restore correct folding, rescuing mutants and WT receptor from this oligomer. Rat WT retains the ability to oligomerize (since human and mouse mutants exert a DN effect on rat (r) WT sequence) but, unlike human or mouse, escapes the DN effect of GnRH receptor (Gn-RHR) mutants because rGnRHR mutants route to the plasma membrane with higher efficiency than mouse or human mutants. These distinct behaviors of mouse and rat GnRHRs (distinguished by only four semi- or non-conservative amino acid differences) led us to assess the role of each amino acid. The difference in both routing and the DN effect appears mediated primarily by Ser216 in the rGnRHR. The homologous amino acid in the hGn-RHR is also Ser and is compensated for by the primate-unique insertion of Lys191 that, alone, dramatically decreases routing of the receptor. These studies establish the relation between the DN effect and altered receptor trafficking and explain why hGnRHR is more susceptible to defective trafficking by disease-related point mutations than rodent counterparts.

Original languageEnglish
Pages (from-to)24506-24514
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number26
DOIs
StatePublished - Jul 1 2005
Externally publishedYes

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LHRH Receptors
Rats
Membranes
Amino Acids
Oligomerization
Cell membranes
Oligomers
Hypogonadism
Point Mutation
Endoplasmic Reticulum
Primates
Rodentia
Cell Membrane
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Parallel regulation of membrane trafficking and dominant-negative effects by misrouted gonadotropin-releasing hormone receptor mutants. / Knollman, Paul E.; Janovick, Jo Ann; Brothers, Shaun P; Conn, P. Michael.

In: Journal of Biological Chemistry, Vol. 280, No. 26, 01.07.2005, p. 24506-24514.

Research output: Contribution to journalArticle

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