The research programs of the Endocrinology and Reproduction Research Branch (ERRB) address the molecular and cellular mechanisms involved in hormone secretion and action. Major topics of interest include the mechanisms of action of peptide hormones in endocrine target cells, the structure-function relationships of peptide and glycoprotein hormones, and the regulation of pituitary hormone synthesis and secretion. At the molecular level, the branch performs research on the plasma-membrane receptors and intracellular signaling processes that control the growth, differentiation, secretion, and metabolism of endocrine target cells. ERRB investigators analyze the mechanisms of action of peptide and glycoprotein hormones, the role of neuropeptides in hypothalamic-pituitary and gonadal regulation, the control of gonadal and adrenal function by pituitary hormones, the renin-angiotensin system and aldosterone secretion, and the mechanisms and roles of protein phosphorylation and sulfonation in metabolic regulation and signal transduction.

The branch’s recent achievements include advances in the molecular basis of hormone action and receptor function, phosphoinositide-protein interactions, ion channels and calcium signaling, and the neurochemical basis of learning and memory. ERRB researchers have developed novel approaches for the analysis of inositol lipid dynamics and lipid-protein interactions in living cells and have provided new insights into the mechanism whereby Raf is recruited to Ras at the plasma membrane. They have identified several structural determinants of G protein-coupled receptor (GPCR) activation and signaling and determined the location and function of agonist-induced AT1 and AT2 receptor phosphorylation. The operation of the hypothalamic GnRH pulse generator was shown to depend on autocrine regulation via GnRH receptors expressed in hypothalamic neurons and to be inhibited by GnRH antagonists. Members of the branch found that the expression of the human luteinizing hormone receptor in gonadal cells is controlled by orphan nuclear receptors and that the promoter domain of the human prolactin receptor is subject to tissue-specific regulation and gives rise to multiple receptor subtypes. Two novel gonadotropin-regulated genes were identified as an RNA helicase and a long-chain fatty acyl CoA synthetase, which are expressed in Leydig cells and seminiferous tubule cells.

The protein kinase C substrate, neurogranin, was found to serve as a calmodulin (CAM) binding protein and to regulate the activity of calcium/CAM dependent protein kinase II, an important regulator of synaptic function and memory storage. Researchers showed that a neurogranin knock-out mouse had defective activation of the enzyme as well as impaired learning and memory. Both learning and memory depend on neurogranin for enhancement of synaptic responses by Ca2+/CAM-mediated phosphorylation of specific neuronal substrates.

The branch made significant progress in the characterization of voltage-gated and ligand-gated purinergic channels expressed in pituitary cells and their roles in spontaneous electrical activity and action potential-controlled calcium signaling, cyclic nucleotide production, and hormone secretion. The cell type–specific expression of channels, specifically BK and A potassium channels, proved to be critical in determining the pattern of action potential-driven calcium signals as well as calcium-dependent cyclic nucleotide production and basal hormone secretion. The core promoters and downstream regulators of the two human genes encoding isozymes that produce the universal sulfonate donor molecular, PAPS, were established and a novel sulfotransferase that sulfonates cholesterol was identified and characterized.