Introduction to the Year In Basic Science Series . . . 2009

Abstract

This year represents the second, of what we expect to be an annual series, of articles based on The Endocrine Society annual meeting presentations that highlight recent advances in vibrant basic science areas in endocrinology. For ENDO 09, two general areas with broad appeal and significance to our members were chosen: neuroendocrinology and G protein-coupled receptors. The invited participants were charged with presenting and discussing important papers that were published approximately during the year leading up to the most recent annual meetings (June 2009) and to put them into broad perspective for the greater endocrine community. Two distinguished members, Jeffrey Blaustein and Robert Millar, continued on last year’s successful features by synthesizing the top findings in their fields, and these articles are based on their annual meeting presentations. Interestingly, there were several points of intersection in these topics and chosen papers, as advances in the neuroendocrinology of reproduction have been coupled to identification and/or characterization of additional novel G protein-coupled receptors. In both presentations, fundamental basic science findings deriving from structural studies and signaling pathways are linked to broad endocrine physiology issues and to potential use in clinical treatment and therapeutics.

The first article, “The Year In Neuroendocrinology” by Jeff Blaustein (1) is based on a broad survey of many neuroendocrinologists throughout the word, who suggested both subject areas and specific papers for consideration. From the suggestions of approximately 30 individuals, there was consensus on three broad areas to highlight, including neural mechanisms of action of estradiol, modulation of GnRH neurons and GnRH biological effects, and epigenetics and the brain—or how previous exposure to hormonal or environmental cues impacts on brain function. In the first general area, exciting findings include how nontraditional estrogen receptors (ERs) such as a DNA-binding deficient ERα and GPR30, the G protein-coupled receptor (GPCR), as well as neurosteroids, fulfill specific biological functions in the brain and how estradiol may act on one neuron that secretes molecules that influence the function of separate, ER-negative neurons downstream. In the area of GnRH regulation, highlights include the roles of kisspeptin in GnRH regulation outside of puberty, the potential role of neurokinin B in puberty, and the potential role of RFamide as a negative regulator of GnRH neuron activity. Finally, attention was focused on a set of basic and translational papers that appears to link the epigenetic regulation of the hippocampal glucocorticoid receptor first described in rodents (i.e. increased receptor expression positively linked to parental care) to studies in humans, in which significantly lower levels of glucocorticoid receptor expression occur in suicide victims who were abused as children.

In the second article in this series, “The Year In G Protein-Coupled Receptors,” by Robert Millar and Claire Newton (2), a somewhat broader approach was taken, which highlighted the broad areas of research among all GPCRs, as well as identifying potential areas for future development. This broad topic, encompassing more than 8000 articles this year alone, was focused on three broad areas including new atomic level structures of GPCRs, modulation of selective signaling, and regulation of GPCR membrane expression. For the first point, GPCR structures have recently become available for several structures and demonstrate the potential versatility of the solved structures and their ligand-binding pockets in predicting agonists vs. antagonists and in developing possible therapeutics. Next, the discovery of oligomeric complexes of these receptors has been an exciting concept that has clear implications for receptor signaling. The identification of two classes of molecules that impact GPCR expression at the cell surface (i.e. shuttling proteins that transport the receptors to the cell surface and pharmacochaperones that rescue mutant and underexpressing GPCRs) have provided new understanding to how receptor numbers are regulated and present new potential therapeutic targets to modulate receptor function. Finally, some novel GPCRs that have recently become important in endocrinology, including those for glucose and free fatty acids, as well as kisspeptin, neurokinin B, and RFamide, are discussed, neatly linking this article to the topic of neuroendocrinology and reproduction.

These presentations and articles provide a conceptual framework in which to appreciate the recent advances in these fields. Furthermore, the discussions highlight the potential to understand the new molecules and pathways discussed, as well as potential development of new ligands and other compounds to control these pathways as exciting new directions in these vibrant areas of endocrine science.