New paradigm for hormonal disease?
drug target for fertility control, abnormal puberty and
hormone-dependent cancers.
UK company Paradigm Therapeutics has discovered a new G protein-coupled receptor, GPR54, that seems to be required for the regulation of sex hormone secretion. The company hopes that the discovery could open up a path towards new drugs for the control of fertility, abnormal puberty, and hormone-dependent cancers.
Gene mutations that disrupt the normal function of GPR54 cause a lack of production of hormones from the pituitary gland, and have been shown to result in failure to reach sexual maturation in both mice and humans. The findings are published in the New England Journal of Medicine.
Dr Samuel Aparicio, Paradigm's chief scientific officer said that signalling through this receptor is required for the normal production of gonadotropins from the pituitary that occurs at puberty.
"This defines a new receptor in the function of the sex hormones axis, with wide potential as a target for therapeutic intervention in sex steroid relatedconditions," he added.
Paradigm created designer mutations that knocked out the function of theGPR54 gene using mouse embryonic stem cells and then studied the effects in mice. It was found that mice homozygous for the designer mutations failed to undergo normal sexual maturation which, in mammals, occurs at puberty.Organs that normally develop under the effects of sex-steroids secreted atthe time of puberty, such as testes, ovaries and breast epithelium, remainedsmall and in a juvenile state in the mutant mice. The team then studied whether the failure to undergo sexual maturation was due to a problem with gonads and end organs or an absence of sex-steroids, and discovered that an absence of sex steroids was the primary explanation.
This gene is an especially interesting finding because it is a surface receptor and at least one of its natural ligands is itself a peptide hormone. This opens up the possibility that GPR54 is part of a new hormonal control loop between peripheral organs and the master control circuits within the pituitary andhypothalamus.
The work was conducted in partnership with the Reproductive Endocrinology Unit at Massachusetts General Hospital in Boston, US.
