Preferential β-arrestin signalling at low receptor density revealed by functional characterization of the human FSH receptor A189 V mutation

Mol Cell Endocrinol. 2011 Jan 1;331(1):109-18. doi: 10.1016/j.mce.2010.08.016. Epub 2010 Aug 27.

Abstract

The A189 V inactivating mutation of the human FSH receptor (FSHR) leads to subfertility in men and primary ovarian failure in women. This mutation has previously been associated with intracellular retention of the FSHR and impaired cAMP production. Here, we show that the A189 V FSHR stably expressed in HEK293N cells provoked ERK MAP kinases phosphorylation through β-arrestins, independently of the canonical cAMP/PKA pathway. Interesting, both the A189 V and wild-type (Wt) FSHRs selectively activated cAMP-independent ERK phosphorylation when expressed at low plasma membrane densities. These data indicate that the selective intracellular signalling triggered by the A189 V FSHR resulted from reduced membrane expression rather than by switching receptor coupling. Hence, receptor density at the plasma membrane might control the balance between distinct signal transduction mechanisms. Furthermore, our results help to clarify why mutations of FSHβ are more deleterious to human fertility than the FSHR A189 V mutation which preserves parts of receptor signalling repertoire.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics*
  • Animals
  • Arrestins / metabolism*
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Follicle Stimulating Hormone / pharmacology
  • HEK293 Cells
  • Humans
  • Kinetics
  • Male
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Phosphorylation / drug effects
  • Receptors, FSH / chemistry
  • Receptors, FSH / genetics*
  • Receptors, FSH / metabolism*
  • Signal Transduction* / drug effects
  • Swine
  • Transfection
  • beta-Arrestins

Substances

  • Arrestins
  • Mutant Proteins
  • Receptors, FSH
  • beta-Arrestins
  • Follicle Stimulating Hormone
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Extracellular Signal-Regulated MAP Kinases