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endocrinology and reproduction research branch

Kevin Catt, MD, PhD, Chief

The Endocrinology and Reproduction Research Branch (ERRB) investigates the molecular and cellular mechanisms of reproductive hormone action, the structure-function properties and signaling pathways of peptide hormone receptors, and the roles of phosphorylation and sulfonation in metabolic regulation and signal transduction.

Tamas Balla’s Section on Molecular Signal Transduction has used targeted tethering of InsP3-binding protein motifs to the surface of specific organelles to investigate the role of IP3 compartmentalization in calcium signaling, revealing that the N-terminal ligand-binding domain of the InsP3 receptor channel can control calcium release via InsP3 receptors. The group also studied the PI 4-kinase type-IIIbeta enzyme and established a functional yeast assay to study the mammalian protein. Guided mutagenesis of the catalytic domain created an enzyme insensitive to wortmannin, which also accepts ATP analogs that cannot be used by the endogenous enzymes. These molecular tools will facilitate analysis of the enzyme’s regulation and function in mammalian cells.

Kevin Catt’s Section on Hormonal Regulation investigates the molecular mechanisms by which specific agonists induce G protein–coupled receptor (GPCR)–mediated signaling pathways, in particular those initiated by agonist activation of the GPCRs for angiotensin II (Ang II) and gonadotropin-releasing hormone (GnRH). Current studies focus on the interactions and signaling between these GPCRs and receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) as well as on the biosynthesis, endocytosis, and recycling of GPCRs and the nature of their associated signaling proteins. Recent findings include the operation of the GnRH pulse generator in olfactory placode–derived GnRH neurons and the definition of signaling pathways by which Ang II and GnRH cause transactivation of the EGFR in specific cell types.

Maria Dufau’s Section on Molecular Endocrinology has found that demethylation and histone modifications derepress human LHR gene promoter activity, with dissociation of the inhibitory HDACs/mSin3A complex and DNMT1 associated with Sp1 at the promoter, thus linking DNA methylation and histone modifications to transcriptional activation of LHR expression. The development of azoospermic mice null for the testis-specific RNA helicase (GRTH/Ddx25) revealed the helicase’s function as a critical mRNA binding protein for regulation of translational processes essential for spermatid elongation, insights relevant to male reproduction and fertility. In human breast tumor tissue and cells, the ratio of short (inhibitory) to long (activating) forms of the human prolactin receptor were lower than in normal tissue, providing an index for evaluation of breast cancer. A reduction in the short form’s inhibition of long form activation may be operative in mammary tumors.

Kuo-Ping Huang’s Section on Metabolic Regulation studies synaptic plasticity in neurogranin (Ng) knockout mice that exhibit deficits in learning and memory (L&M) of spatial tasks and long-term potentiation (LTP). Hippocampal Ng concentrations correlate highly with L&M performance, and enriched environments increase hippocampal Ng content, behavioral test performance, and expression of LTP. Ng promotes rises in neuronal free Ca²⁺ that enhance synaptic responses and favor induction of LTP over long-term depression. Ng may regulate neuronal signaling and enhance synaptic plasticity because, at a higher Ng concentration, the formation of Ng/CaM complexes effectively raises [Ca²⁺]_i at any given Ca²⁺ influx. The consequent signal amplification enhances synaptic plasticity as well as L&M.

Stanko Stojilkovic’s Section on Cellular Signaling studies the roles of ATP-gated purinergic receptors in the control of pace-making activity and hormone secretion in pituitary cells. The section identified critical residues for ATP binding at the extracellular domain of recombinant purinergic receptors as well as the mechanism of receptor deactivation and desensitization and the pathways involved in degradation of extracellular ATP. The group determined the dependence of guanylyl cyclase activity on intracellular calcium, nitric oxide, and phosphorylation by protein kinase A and of spontaneous electrical activity on cyclic nucleotide–dependent signaling pathways. Studies on calcium signaling by endothelins and growth hormone revealed their relevance in controlling voltage-gated calcium influx and gene expression through autocrine/paracrine mechanisms.

Charles Strott’s Section on Steroid Regulation investigates molecular mechanisms and biologic implications of sulfonation, a fundamental process in the biotransformation of endobiotics as well as of drugs and xenobiotics. Studies on the crystal structure of human cholesterol sulfotransferase (SULT2B1b) in the presence of pregnenolone and PAP provided a rationale for specificity differences between prototypical SULT2A1 and SULT2B1 isoforms. The group analyzed, in the mouse, conservation of the hydroxysteroid sulfotransferase SULT2B1 gene structure, its pre- and postnatal expression, and kinetics isoforms and compared them with prototypical SULT2A. The group studied cholesterol sulfotransferase (SULT2B1b) expression in human skin, epidermal keratinocytes, and platelets.