Heterodimerization Between the Lutropin and Follitropin Receptors is Associated With an Attenuation of Hormone-Dependent Signaling

Abstract

The LH receptor (LHR) and FSH receptor (FSHR) are each G protein-coupled receptors that play critical roles in reproductive endocrinology. Each of these receptors has previously been shown to self-associate into homodimers and oligomers shortly after their biosynthesis. As shown herein using bioluminescence resonance energy transfer to detect protein-protein interactions, our data show that the LHR and FSHR, when coexpressed in the same cells, specifically heterodimerize with each other. Further experiments confirm that at least a portion of the cellular LHR/FSHR heterodimers are present on the cell surface and are functional. We then sought to ascertain what effects, if any, heterodimerization between the LHR and FSHR might have on signaling. It was observed that when the LHR was expressed under conditions promoting the heterodimerization with FSHR, LH or human chorionic gonadotropin (hCG) stimulation of Gs was attenuated. Conversely, when the FSHR was expressed under conditions promoting heterodimerization with the LHR, FSH-stimulated Gs activation was attenuated. These results demonstrate that the coexpression of the LHR and FSHR enables heterodimerizaton between the 2 gonadotropin receptors and results in an attenuation of signaling through each receptor.

FSH for the Treatment of Male Infertility

“…This equivalence is evident in vitro, especially when they are compared in cell systems expressing both FSHR and LHCGR, such as the human granulosa cells, and in vivo in clinical, non-inferiority studies. While, in the first case, FSH-induced signals may be modulated through the molecular cooperation of the two receptors [90,91] that attenuates the glycoform-specific activation of downstream signaling cascades [92], data obtained in vivo may be affected by the complex network of hormone actions and by the genetic background of the host, impeding a proper dissection of the hormone-specific effects. Most of the results demonstrating specific biological effects of FSH iso/glycoforms were obtained in cell models expressing only the FSHR and lacking LHCGR expression [64,79].…”

Oligomerization of GPCRs involved in endocrine regulation

“…Furthermore, heteromerization of FSH and LHCGR co-expressed in in vitro cell systems have been observed (Feng et al 2013, Mazurkiewicz et al 2015. In granulosa cells, LHCGR and FSHR are co-expressed and LHCGR/FSHR interaction is speculated to play a role during granulosa cell differentiation.…”

“…The nigrostriatal system is critical for movement and the mesolimbic and mesocortical neurons play a major role in cognitive functions including feeding, affect, reward, sleep, attention, memory and , 2004, Tao et al 2004, Feng et al 2013, Mazurkiewicz et al 2015) LHCGR-LHCGR LHCGR-FSHR (Ji et al 2002, 2004, Tao et al 2004, Feng et al 2013, Mazurkiewicz et al 2015 (Guo et al 2003(Guo et al , 2005 and a multitude of heteromers (Perreault et al 2014), e.g. with the D1R, D4R, D5R, adenosine A2 receptor (A2R), serotonin 2A receptor (5HT-2AR), OTR, and the histamine H3 receptor (H3R).…”

G Protein–Coupled Receptor Multimers: A Question Still Open Despite the Use of Novel Approaches

“…All three glycoprotein hormone receptors form homomers and heteromers in transfected cells (Urizar et al, 2005;Feng et al, 2013). However, only heteromerization between FSHR-LHR might be physiologically relevant as both receptors are shortly coexpressed in granulosa cells during follicle maturation (Thiruppathi et al, 2001).…”