GPH+rec.

1. Overview of Gonadotropin Signalling

  • Examines the specificity and promiscuity of gonadotropin receptors (FSH, LH, and TSH).

  • Understands how the hormone recognition by receptors occurs.

  • Highlights the significance of specific binding between hormones and receptors yet notes instances where promiscuity occurs.

2. Gonadotropin Receptors

2.1 Types of Receptors

  • Glycoprotein hormone receptors (GpHRs) include:

    • Follicle-stimulating hormone receptor (FSHR)

    • Luteinizing hormone receptor (LH/CGR)

    • Thyrotropin receptor (TSHR)

  • GpHRs are characterized by:

    • Ectodomain containing leucine-rich repeat motifs (LRRs)

    • Canonical heptahelical serpentine domain typical of GPCRs

2.2 Role of Ectodomain and Serpentine Domain

  • Ectodomain is crucial for binding specificity of hormones.

  • The serpentine domain is associated with signal transduction.

  • Increased understanding comes from mutations affecting receptor sensitivity and activation.

3. Specificity Barriers and Activations

3.1 Mechanism of Receptor Activation

  • Hormone binding causes a conformational change in the ectodomain.

  • The model initially developed for TSHR applies to the entire GpHR family.

  • High concentrations of gonadotropins, such as hCG, can sometimes lead to unexpected receptor activation.

3.2 Role of Mutations

  • Five mutations in the FSHR serpentine domain lead to increased sensitivity to hCG, TSH, and constitutive activation.

  • Mutations challenge the classical model by showing specificity barriers arise both from the ectodomain and the serpentine domain.

4. Co-evolution of Gonadotropins and Receptors

4.1 Genetic Similarity

  • Beta subunits of TSH, LH, and FSH share about 40% sequence identity.

  • Commonality reflects co-evolution and helps prevent promiscuous signaling.

4.2 Increased Promiscuity

  • Although no cross-signaling occurs under physiological conditions:

    • High concentrations of hCG and TSH can induce inappropriate interactions, leading to hyperthyroidism and ovarian hyperstimulation syndrome (OHSS).

5. Functional Specificity

5.1 Dimerization Phenomenon

  • LH and FSH receptors can form homo- and heterodimers, potentially altering functional characteristics.

  • Dimerization associated with negative cooperativity affects agonist binding.

5.2 Perspectives and Investigations

  • Future studies should address:

    • The effects of FSH receptor variants in iatrogenic ovarian hyperstimulation syndrome (OHSS).

    • The role of heterodimers during ovulation in granulosa cells.

    • Mechanisms by which LHR dimers respond to high concentrations of hCG.

6. Acknowledgements and Support

  • Acknowledges contributions from laboratory staff and clinicians.

  • Supported by Belgian programs and European Community grants.

Detailed Overview of Gonadotropin Signalling

This section examines the specificity and promiscuity of gonadotropin receptors, specifically focusing on Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), and Thyroid-stimulating hormone (TSH). It provides an in-depth understanding of the molecular mechanisms behind hormone recognition by their corresponding receptors. Importantly, it highlights the significance of high-affinity and specific binding between hormones and receptors while also discussing instances where receptor promiscuity occurs, which can have physiological implications.

Gonadotropin Receptors

2.1 Types of Receptors

Glycoprotein hormone receptors (GpHRs) include:

  • Follicle-stimulating hormone receptor (FSHR): Plays a critical role in regulating reproductive processes including gametogenesis.

  • Luteinizing hormone receptor (LH/CGR): Involved in controlling the ovulatory cycle and fertility.

  • Thyrotropin receptor (TSHR): Essential for regulating thyroid function and metabolic activity.

GpHRs are characterized by:

  • An ectodomain containing leucine-rich repeat motifs (LRRs), facilitating the specific interaction with hormones.

  • A canonical heptahelical serpentine domain typical of G protein-coupled receptors (GPCRs), crucial for signal transduction.

2.2 Role of Ectodomain and Serpentine Domain

The ectodomain is crucial for the binding specificity of hormones, as it determines the receptor's affinity and selectivity for particular ligands. The serpentine domain is integral for signal transduction, launching a cascade of intracellular events upon hormone binding. Increased understanding of these mechanisms has emerged from studies involving mutations that affect both receptor sensitivity and activation, allowing researchers to delineate between normal signaling routes and aberrant pathways resulting from mutations.

Specificity Barriers and Activations

3.1 Mechanism of Receptor Activation

Upon hormone binding, a conformational change occurs in the ectodomain that activates the receptor. The model initially formulated for TSHR applies across the GpHR family, indicating shared pathways. Notably, high concentrations of gonadotropins, such as human Chorionic Gonadotropin (hCG), can provoke unexpected receptor activation, which underscores the complexity of hormone-receptor interactions.

3.2 Role of Mutations

Studies have identified five distinct mutations within the FSHR serpentine domain that lead to increased sensitivity to hCG, TSH, and unintended constitutive activation of the receptor. These findings challenge the classical model of receptor specificity and highlight that specificity barriers can arise from both the ectodomain and serpentine domains, suggesting a dual mechanism that governs receptor function.

Co-evolution of Gonadotropins and Receptors

4.1 Genetic Similarity

The beta subunits of TSH, LH, and FSH exhibit about 40% sequence identity, reflecting their genetic similarities that arise from co-evolution. This commonality plays a significant role in preventing promiscuous signaling between different receptors under normal physiological conditions.

4.2 Increased Promiscuity

Although cross-signaling is typically absent under physiological conditions, it is essential to note that elevated concentrations of hormones like hCG and TSH can trigger inappropriate receptor interactions. This can lead to pathological conditions such as hyperthyroidism and ovarian hyperstimulation syndrome (OHSS), illustrating the clinical relevance of gonadotropin signalling.

Functional Specificity

5.1 Dimerization Phenomenon

Receptors for LH and FSH are capable of forming both homo- and heterodimers, a process that may significantly alter their functional characteristics. Dimerization is associated with negative cooperativity, a phenomenon where the binding of one ligand reduces the affinity of subsequent ligand binding.

5.2 Perspectives and Investigations

Future studies are warranted to address critical questions including:

  • The effects of variants in the FSH receptor on the incidence and severity of iatrogenic ovarian hyperstimulation syndrome (OHSS).

  • The role of heterodimers in mediating signals during ovulation, particularly in granulosa cells.

  • Mechanisms by which LH receptor dimers respond to elevated concentrations of hCG, which may impact fertility treatments.

Acknowledgements and Support

Acknowledges the invaluable contributions from laboratory staff and clinicians who have facilitated this research. This work has been supported by Belgian scientific programs and grants from the European Community, enabling ongoing research in this critical area of endocrinology.