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# Editorial: Pharmacology of endocrine related GPCRs

Francesco de Pascali, Aylin Hanyaloglu, Frédéric Jean-Alphonse, Francesco Potì, Eric Reiter

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## To cite this version:

Francesco de Pascali, Aylin Hanyaloglu, Frédéric Jean-Alphonse, Francesco Potì, Eric Reiter. Editorial: Pharmacology of endocrine related GPCRs. Frontiers in Endocrinology, 2024, 15, pp.1379108. 10.3389/fendo.2024.1379108. hal-04525032

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OPEN ACCESS

EDITED AND REVIEWED BY

Pierre De Meyts,
Université catholique de Louvain,
Belgium

*CORRESPONDENCE

Francesco De Pascali

<figure><img src="image_2.png" /></figure>

francesco.depascali@jefferson.edu

RECEIVED 30 January 2024

ACCEPTED 05 February 2024

PUBLISHED 15 February 2024

CITATION

De Pascali F, Hanyaloglu A, Jean-Alphonse F, Poti F and Reiter E (2024) Editorial: Pharmacology of endocrine related GPCRs. *Front. Endocrinol.* 15:1379108.
doi: 10.3389/fendo.2024.1379108

COPYRIGHT

© 2024 De Pascali, Hanyaloglu, Jean-Alphonse, Poti and Reiter. This is an open-access article distributed under the terms of the [Creative Commons Attribution License (CC BY)](https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Editorial: Pharmacology of
endocrine related GPCRs

Francesco De Pascali¹*, Aylin Hanyaloglu²,
Frederic Jean-Alphonse³,⁴, Francesco Poti⁵ and Eric Reiter³,⁴

¹Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States, ²Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom, ³Physiologie de la Reproduction et des Comportements (PRC), Institut National de Recherche pour l'Agriculture, l'Alimentation, et l'Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS), Université de Tours, Nouzilly, France, ⁴Inria, Inria Saclay-Ile-de-France, Palaiseau, France, ⁵Department of Medicine and Surgery, Unit of Neurosciences, University of Parma, Parma, Italy

KEYWORDS

endocrine system, GPCRs (G protein-coupled receptors), gonadotropin receptors, pharmacoperones, ketogenic diet, prostaglandin E (PGE2) 2

Editorial on the Research Topic

Pharmacology of endocrine related GPCRs

About 30-40% of Food and Drug Administration (FDA)-approved drugs on the market target a G protein-coupled receptor (GPCR), qualifying these membrane-spanning proteins as an important pharmaceutical target (1). GPCRs are expressed in all tissues and control many different physiological functions by virtue of their ability to fine-tune cellular responses to endogenous and exogenous stimuli. GPCRs are activated when a stimulus (photons, odorant molecules, hormones, chemicals, etc.) interacts with the binding site (either orthosteric or allosteric), producing a characteristic conformational change in the GPCR structure that ultimately leads to an intracellular signaling cascade and a physiological output (2). At the same time, the endocrine apparatus is mainly structured as a glandular-hormone-tissue system in which a gland synthesizes the hormone that eventually modifies the function of a tissue. GPCRs are central in such system as they are the receiver of many of the circulating hormones (3). Consequently, issues with GPCR biology often result in endocrine diseases, which highlights the necessity to develop therapeutics to address GPCR-mediated endocrine disorders (4). In view of such unmet needs, this Research Topic aims to spotlight the most up-to-date advances in the pharmacology of endocrine-related GPCRs. It comprises four literature reviews encompassing basic molecular features of endocrine GPCRs and their clinical implications.

The review by Lazzaretti et al. focuses on the pharmacological modulation of gonadotropin receptors, a subfamily of the glycoprotein hormone receptor family that comprises the follicle-stimulating hormone receptor (FSHR) and the luteinizing hormone/choriogonadotropin hormone receptor (LHCGR). The two receptors and their hormones, follicle-stimulating hormone (FSH) for the FSHR, luteinizing hormone, and choriogonadotropin for the LHCGR, virtually control all aspects of human reproduction, both in males and females. Therefore, there is much interest in pharmacologically targeting these receptors for several applications, such as in assisted reproductive techniques, in contraception, or to cure/prevent reproductive-associated diseases. The authors describe a
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Check for updates

OPEN ACCESS

EDITED AND REVIEWED BY

Pierre De Meyts,
Université catholique de Louvain,
Belgium

*CORRESPONDENCE

Francesco De Pascali

<figure><img src="image_5.png" /></figure>

francesco.depascali@jefferson.edu

RECEIVED 30 January 2024

ACCEPTED 05 February 2024

PUBLISHED 15 February 2024

CITATION

De Pascali F, Hanyaloglu A, Jean-Alphonse F, Poti F and Reiter E (2024) Editorial: Pharmacology of endocrine related GPCRs. *Front. Endocrinol.* 15:1379108.
doi: 10.3389/fendo.2024.1379108

COPYRIGHT

© 2024 De Pascali, Hanyaloglu, Jean-Alphonse, Poti and Reiter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Editorial: Pharmacology of endocrine related GPCRs

Francesco De Pascali¹*, Aylin Hanyaloglu²,
Frederic Jean-Alphonse³,⁴, Francesco Poti⁵ and Eric Reiter³,⁴

¹Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States, ²Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom, ³Physiologie de la Reproduction et des Comportements (PRC), Institut National de Recherche pour l'Agriculture, l'Alimentation, et l'Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS), Université de Tours, Nouzilly, France, ⁴Inria, Inria Saclay-Ile-de-France, Palaiseau, France, ⁵Department of Medicine and Surgery, Unit of Neurosciences, University of Parma, Parma, Italy

KEYWORDS

endocrine system, GPCRs (G protein-coupled receptors), gonadotropin receptors, pharmacoperones, ketogenic diet, prostaglandin E (PGE2) 2

Editorial on the Research Topic

Pharmacology of endocrine related GPCRs

About 30-40% of Food and Drug Administration (FDA)-approved drugs on the market target a G protein-coupled receptor (GPCR), qualifying these membrane-spanning proteins as an important pharmaceutical target (1). GPCRs are expressed in all tissues and control many different physiological functions by virtue of their ability to fine-tune cellular responses to endogenous and exogenous stimuli. GPCRs are activated when a stimulus (photons, odorant molecules, hormones, chemicals, etc.) interacts with the binding site (either orthosteric or allosteric), producing a characteristic conformational change in the GPCR structure that ultimately leads to an intracellular signaling cascade and a physiological output (2). At the same time, the endocrine apparatus is mainly structured as a glandular-hormone-tissue system in which a gland synthesizes the hormone that eventually modifies the function of a tissue. GPCRs are central in such system as they are the receiver of many of the circulating hormones (3). Consequently, issues with GPCR biology often result in endocrine diseases, which highlights the necessity to develop therapeutics to address GPCR-mediated endocrine disorders (4). In view of such unmet needs, this Research Topic aims to spotlight the most up-to-date advances in the pharmacology of endocrine-related GPCRs. It comprises four literature reviews encompassing basic molecular features of endocrine GPCRs and their clinical implications.

The review by Lazzaretti et al. focuses on the pharmacological modulation of gonadotropin receptors, a subfamily of the glycoprotein hormone receptor family that comprises the follicle-stimulating hormone receptor (FSHR) and the luteinizing hormone/choriogonadotropin hormone receptor (LHCGR). The two receptors and their hormones, follicle-stimulating hormone (FSH) for the FSHR, luteinizing hormone, and choriogonadotropin for the LHCGR, virtually control all aspects of human reproduction, both in males and females. Therefore, there is much interest in pharmacologically targeting these receptors for several applications, such as in assisted reproductive techniques, in contraception, or to cure/prevent reproductive-associated diseases. The authors describe a
comprehensive set of molecules with different pharmacological
properties that have been developed to selectively control
gonadotropin receptor activity. These include agonists and
antagonists, but the focus of the study is on the efforts made to
develop suitable allosteric modulators to be used for clinical
purposes. The authors describe all the different implications the
allosteric modulation may produce on FSHR and LHCGR activity,
as well as their influence on their cognate receptor's structure. The
authors conclude the review with some up-to-date insights into
FSHR and LHCGR heterodimerization and how such structural
occurrence can contribute to allosteric modulation.

In the review by Ulloa-Aguirre et al., the authors describe some specific endocrine disorders that originate from misfolded GPCRs that are unable to be located at the plasma membrane of the cells. Commonly, this happens when the cell quality control system (QCS), which is a complex protein system comprising chaperons, co-factors, enzymes, etc., identifies a GPCR that has an altered structure and reroutes its trafficking to degradation instead of the plasma membrane. Endocrine disorders associated with misfolded GPCRs are familial hypocalciuric hypercalcemia, X-linked nephrogenic diabetes insipidus, and familial glucocorticoid resistance, among many others. Furthermore, the authors center the discussion on the experimental strategies that have been implemented to restore the presence of the misfolded GPCRs partially or completely at the plasma membrane as an approach to treat the associated endocrine diseases. The authors concluded that one of the most promising and accessible strategies would be the one that employs pharmacoperones as treatment agents. These are molecules able to correct the folding of misfolded proteins, avoiding their accumulation or degradation by the QCS. They can be either agonists, antagonists, or allosteric modulators and might represent a winning strategy to cure endocrine diseases associated with missorted proteins.

The review by Spigoni et al. addresses the interplay between a
ketogenic diet and the activation of endocrine-related GPCRs. The
ketogenic diet is so-called because such an eating regimen leads to
an overproduction of ketone bodies, which represent alternative
energy sources for the human organism and a possible strategy for
weight management. The authors highlight recent evidence
supporting the activation of GPR109A, GPR41, and GPR43 by
ketone bodies and their involvement in the endocrine control of
lipid metabolism and inflammation. Indeed, the β-hydroxybutyrate
(β-OHB) mediated activation of GPR109A provokes a decrease in
adipocytic lipase activity, while the simultaneous activation of
GPR43 by acetoacetate raises lipid consumption. Furthermore,
the agonist activity of β-OHB on GPR109A may lead to anti-
inflammatory effects, often associated with a ketogenic diet.
In conclusion, with this review, the authors point out the
pharmacological and molecular mechanism implications of GPCR
activity with regard to some of the outcomes generally associated
with a ketogenic regimen.

In the last review by Wang et al., the authors discuss the role of
prostaglandin E2 (PGE2) in the endocrine regulation of fluid and

blood dynamics. PGE2 is a lipid-derived hormone that controls a
plethora of physiological functions. One of the most canonical is the
inhibition of the activity of cyclooxygenases, resulting in the control
of inflammation and pain. For the purpose of this review, the
authors focus on the effects of PGE2 as an agonist of the four
subtypes of the E-prostanoid (EP₁₋₄) receptors in the control of
hemo-and fluid dynamics in the various cell and tissue types where
the EP receptor subtypes are differently expressed. Through a
comprehensive analysis of the available scientific literature, the
authors conclude that PGE2 mediates fluid and blood pressure
homeostasis in either a positive or negative manner. Furthermore,
the four EP receptor subtypes are responsible for selectively
contributing to the different outputs, putting them at a glance to
be possible targets of endocrine disorders related to fluid and
blood dynamics.

In summary, the four review articles that constitute this Research
Topic highlight the important role GPCRs play in regulating the
endocrine system. The pharmacological targeting of such receptors is
an attractive approach that researchers and clinicians are interested
in pursuing. At the same time, more effort is needed to understand
the basic biology and pharmacology of GPCRs as a starting point to
develop safer and more efficacious drugs for the treatment of
endocrine disorders.

Author contributions

FP: Writing – original draft, Writing – review & editing.

AH: Writing – original draft, Writing – review & editing. FJ-A:

Writing – original draft, Writing – review & editing. FP: Writing –

original draft, Writing – review & editing. ER: Writing – original

draft, Writing – review & editing.

Conflict of interest

The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.

The author(s) declared that they were an editorial board
member of Frontiers, at the time of submission. This had no
impact on the peer review process and the final decision.

Publisher's note

All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
comprehensive set of molecules with different pharmacological
properties that have been developed to selectively control
gonadotropin receptor activity. These include agonists and
antagonists, but the focus of the study is on the efforts made to
develop suitable allosteric modulators to be used for clinical
purposes. The authors describe all the different implications the
allosteric modulation may produce on FSHR and LHCGR activity,
as well as their influence on their cognate receptor's structure. The
authors conclude the review with some up-to-date insights into
FSHR and LHCGR heterodimerization and how such structural
occurrence can contribute to allosteric modulation.

In the review by Ulloa-Aguirre et al., the authors describe some specific endocrine disorders that originate from misfolded GPCRs that are unable to be located at the plasma membrane of the cells. Commonly, this happens when the cell quality control system (QCS), which is a complex protein system comprising chaperons, co-factors, enzymes, etc., identifies a GPCR that has an altered structure and reroutes its trafficking to degradation instead of the plasma membrane. Endocrine disorders associated with misfolded GPCRs are familial hypocalciuric hypercalcemia, X-linked nephrogenic diabetes insipidus, and familial glucocorticoid resistance, among many others. Furthermore, the authors center the discussion on the experimental strategies that have been implemented to restore the presence of the misfolded GPCRs partially or completely at the plasma membrane as an approach to treat the associated endocrine diseases. The authors concluded that one of the most promising and accessible strategies would be the one that employs pharmacoperones as treatment agents. These are molecules able to correct the folding of misfolded proteins, avoiding their accumulation or degradation by the QCS. They can be either agonists, antagonists, or allosteric modulators and might represent a winning strategy to cure endocrine diseases associated with missorted proteins.

The review by Spigoni et al. addresses the interplay between a
ketogenic diet and the activation of endocrine-related GPCRs. The
ketogenic diet is so-called because such an eating regimen leads to
an overproduction of ketone bodies, which represent alternative
energy sources for the human organism and a possible strategy for
weight management. The authors highlight recent evidence
supporting the activation of GPR109A, GPR41, and GPR43 by
ketone bodies and their involvement in the endocrine control of
lipid metabolism and inflammation. Indeed, the β-hydroxybutyrate
(β-OHB) mediated activation of GPR109A provokes a decrease in
adipocytic lipase activity, while the simultaneous activation of
GPR43 by acetoacetate raises lipid consumption. Furthermore,
the agonist activity of β-OHB on GPR109A may lead to anti-
inflammatory effects, often associated with a ketogenic diet.
In conclusion, with this review, the authors point out the
pharmacological and molecular mechanism implications of GPCR
activity with regard to some of the outcomes generally associated
with a ketogenic regimen.

In the last review by Wang et al., the authors discuss the role of
prostaglandin E2 (PGE2) in the endocrine regulation of fluid and

blood dynamics. PGE2 is a lipid-derived hormone that controls a
plethora of physiological functions. One of the most canonical is the
inhibition of the activity of cyclooxygenases, resulting in the control
of inflammation and pain. For the purpose of this review, the
authors focus on the effects of PGE2 as an agonist of the four
subtypes of the E-prostanoid (EP₁₋₄) receptors in the control of
hemo-and fluid dynamics in the various cell and tissue types where
the EP receptor subtypes are differently expressed. Through a
comprehensive analysis of the available scientific literature, the
authors conclude that PGE2 mediates fluid and blood pressure
homeostasis in either a positive or negative manner. Furthermore,
the four EP receptor subtypes are responsible for selectively
contributing to the different outputs, putting them at a glance to
be possible targets of endocrine disorders related to fluid and
blood dynamics.

In summary, the four review articles that constitute this Research
Topic highlight the important role GPCRs play in regulating the
endocrine system. The pharmacological targeting of such receptors is
an attractive approach that researchers and clinicians are interested
in pursuing. At the same time, more effort is needed to understand
the basic biology and pharmacology of GPCRs as a starting point to
develop safer and more efficacious drugs for the treatment of
endocrine disorders.

Author contributions

FP: Writing – original draft, Writing – review & editing.

AH: Writing – original draft, Writing – review & editing. FJ-A:

Writing – original draft, Writing – review & editing. FP: Writing –

original draft, Writing – review & editing. ER: Writing – original

draft, Writing – review & editing.

Conflict of interest

The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.

The author(s) declared that they were an editorial board
member of Frontiers, at the time of submission. This had no
impact on the peer review process and the final decision.

Publisher’s note

All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
References

1. Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. *Nat Rev Drug Discovery*. (2017) 16:829–42. doi: 10.1038/nrd.2017.178

2. Wingler LM, Lefkowitz RJ. Conformational basis of G protein-coupled receptor signaling versatility. *Trends Cell Biol*. (2020) 30:736–47. doi: 10.1016/j.tcb.2020.06.002

3. Tse LH, Wong YH. GPCRs in autocrine and paracrine regulations. *Front Endocrinol*. (2019) 10:428. doi: 10.3389/fendo.2019.00428

4. Vassart G, Costagliola S. G protein-coupled receptors: mutations and endocrine diseases. *Nat Rev Endocrinol*. (2011) 7:362–72. doi: 10.1038/nrendo.2011.20
References

1. Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. *Nat Rev Drug Discovery*. (2017) 16:829–42. doi: 10.1038/nrd.2017.178

2. Wingler LM, Lefkowitz RJ. Conformational basis of G protein-coupled receptor signaling versatility. *Trends Cell Biol*. (2020) 30:736–47. doi: 10.1016/j.tcb.2020.06.002

3. Tse LH, Wong YH. GPCRs in autocrine and paracrine regulations. *Front Endocrinol*. (2019) 10:428. doi: 10.3389/fendo.2019.00428

4. Vassart G, Costagliola S. G protein-coupled receptors: mutations and endocrine diseases. *Nat Rev Endocrinol*. (2011) 7:362–72. doi: 10.1038/nrendo.2011.20