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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. |