Preferential β-arrestin signalling at low receptor density revealed by functional characterization of the human FSH receptor A189 V mutation.
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.
Tranchant
Thibaud
T
BINGO Group, INRA, UMR85, Unité Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France.
Durand
Guillaume
G
Gauthier
Christophe
C
Crépieux
Pascale
P
Ulloa-Aguirre
Alfredo
A
Royère
Dominique
D
Reiter
Eric
E
D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008297:Male; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D011962:Receptors, FSH / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D014162:Transfection; D000071557:beta-Arrestins
D019390:Arrestins; D050505:Mutant Proteins; D011962:Receptors, FSH; D000071557:beta-Arrestins; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases