Zero-length cross-linking of the LH receptor reveals tight interactions between extracellular and transmembrane domains during receptor activation

Karges, Beate; Gidenne, Stephane; Aumas, Chantal; Kelly, P. A.; Milgröm, Edwin; Debatin, Klaus‐Michael; Karges, Wölfram; Roux, Nicolas

doi:10.1055/s-2005-920489

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“…According to a model elaborated initially for the TSHR (Vlaeminck et al 2002), and later extended to the GpHR family , Karges et al 2005, binding of the hormone to the receptor would trigger a conformational change in a motif of the ectodomain, transforming it into an agonist of the serpentine domain. This model does not require the postulation of a direct interaction of the agonist with the extracellular loops or transmembrane helices of the serpentine domain in order to trigger activation, which has implications for the understanding of the mechanisms of inappropriate stimulation of the FSHR by chorionic gonadotropin in spontaneous ovarian hyperstimulation syndrome (OHSS) (see below).…”

Section: The Bipartite Structure Of Gphrs Andmentioning

confidence: 99%

Specificity and promiscuity of gonadotropin receptors

Costagliola

Urizar²,

Mendive³

et al. 2005

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The dichotomy between hormone recognition by the ectodomain and activation of the G protein by the rhodopsin-like serpentine portion is a well established property of glycoprotein hormone receptors. The specificity barrier avoiding promiscuous activation of the FSH receptor by the high concentration of human chorionic gonadotropin (hCG) prevailing during human pregnancy was thus believed to lie in the ectodomain. In the past two years, mutations responsible for rare spontaneous cases of ovarian hyperstimulation syndromes have partially modified this simple view. Five naturally occurring mutations have been identified which cause an increase in the sensitivity of the FSH receptor to hCG. Surprisingly, these mutations are all located in the serpentine portion of the receptor. In addition to their effect on sensitivity to hCG, they increase sensitivity of the FSH receptor to TSH, and are responsible for activating the receptor constitutively. Together, the available information indicates that the ectodomain and the serpentine domain of the FSH receptor each contribute to the specificity barrier preventing its spurious activation by hCG. While the former is responsible for establishment of binding specificity, the latter introduces a novel notion of functional specificity. Recent data demonstrate that LH and FSH receptors can constitute functional homo-and heterodimers. This suggests the possibility that in cells co-expressing the two receptors, such as granulosa cells, the heterodimers might be endowed with functional characteristics different from those of each homodimer.

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Section: The Bipartite Structure Of Gphrs Andmentioning

confidence: 99%