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Rescue of Function of Mutant Luteinising Hormone Receptors with Deficiencies in Cell Surface Expression, Hormone

Claire Louise Newton1,2,3, Ross Calley Anderson4,5, Annika Kreuchwig6

  • 1Centre for Neuroendocrinology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa, claire.newton@up.ac.za.

Neuroendocrinology
|April 22, 2020
PubMed
Abstract

Insights

Pharmacological chaperones like LHR-Chap can restore cell surface expression and function in luteinising hormone receptor (LHR) mutants. This approach shows promise for treating diseases caused by G protein-coupled receptor (GPCR) mutations.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • G protein-coupled receptor (GPCR) mutations often lead to misfolding and impaired cell surface expression.
  • Pharmacological chaperones can potentially correct these defects by stabilizing protein folding.

Purpose of the Study:

  • To investigate the effectiveness of the pharmacological chaperone LHR-Chap in rescuing cell surface expression of intracellularly retained luteinising hormone receptor (LHR) mutants.
  • To determine if LHR-Chap can restore hormone binding and signaling functions in LHR mutants.

Main Methods:

  • Expression of mutant LHRs in HEK 293-T cells.
  • Assays for cell surface expression (ELISA), hormone binding (radioligand binding), and signaling (inositol phosphate accumulation).
  • Molecular modeling to predict LHR-Chap interactions.

Main Results:

  • LHR-Chap enhanced cell surface expression of specific LHR mutants.
  • Hormone responsiveness was improved in some mutants after LHR-Chap treatment.
  • Mutants with impaired hormone binding or signaling, but normal cell surface expression, responded to LHR-Chap allosteric activation.

Conclusions:

  • LHR-Chap rescues both cell surface expression and function of various LHR mutants.
  • This chaperone therapy demonstrates potential for treating a range of diseases linked to GPCR mutations.
Keywords:
Allosteric agonistG protein-coupled receptor mutationsLuteinising hormone receptorsPharmacological chaperonesPharmacoperonesReproductive dysfunction

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