| Section on Hormonal Regulation | |||
|
RESEARCH The Section on Hormonal Regulation studies the mechanisms of action of peptide hormones, in particular, angiotensin II (Ang II) and gonadotropin-releasing hormone (GnRH). This work involves the analysis of receptor-mediated processes including G protein-dependent and other intracellular signaling pathways, and of receptor desensitization, endocytosis, and trafficking. Ang II is a major regulator of cardiovascular, renal, adrenal, and neuronal function, and acts through two distinct seven transmembrane receptors (AT1and AT2). The AT1 receptor is widely expressed and accounts for the known, largely Gq-mediated, physiological actions of Ang II. In contrast, the AT2 receptor has a more limited distribution, does not internalize, and does not signal through Gq or Gs-coupled transduction pathways. Instead, the AT2 receptor activates tyrosine phosphatases and exerts inhibitory actions on MAP kinases that counteract the proliferative responses elicited by Ang II and growth factors. Current research includes structure-function analyses of the AT1 and AT2 receptors and the mechanisms controlling their phosphorylation and signaling, and studies on the endocytosis and processing of the AT1 receptor. The physical and functional interactions between the AT1 and AT2 receptors, and those between AT1 and growth factor receptors, are also investigated. In addition, the pathways by which Ang II and growth factors (EGF and PDGF) stimulate MAP kinase activity are analyzed in adrenal, hepatic, and transfected cells expressing native and mutant Ang II receptors. These studies are aimed at the elucidation not only of the regulation and properties of the AT1 and AT2 receptors, but also at the understanding of interactions between the two Ang II receptors and other cell-membrane receptors, in particular, those for growth factors such EGF and PDGF. A major component of this research is the exploration of physical as well as functional interactions of the AT receptors with each other, as well as with tyrosine kinase receptors expressed at the plasma membrane. Studies on the GnRH receptor include the characterization of its structure-function and signaling properties, and of its role in the pituitary and hypothalamus in the regulation of gonadotropin secretion. The control of mammalian reproduction depends on the coordinated activity of the 1500 or so GnRH neurons that are present in the hypothalamus, and comprise the GnRH pulse generator. The operation and control of this essential mechanism is analyzed in cultured hypothalamic neurons and immortalized GnRH neurons (GT-1 cells). The latter cells exhibit many of the properties of native GnRH neurons, including that of intrinsic pulsatility and the ability to secrete GnRH in an episodic manner in vitro. This process is highly calcium-dependent and is also influenced by the cyclic AMP system. Much remains to be learned about the receptor-mediated regulation of the GnRH neuron, and of its repertoire of plasma-membrane ion channels that control neuronal excitability. Although the basic mechanism of the GnRH pulse generator is still incompletely defined, recent findings indicate that the autocrine regulatory action of GnRH on its receptors expressed in the GnRH neuron is an important component of this process. The feedback action of estrogen on the pituitary gland and hypothalamus is also a major regulator of gonadotropin secretion, and is exerted at the hypothalamic level through alpha- and beta-estrogen receptors expressed in GnRH neurons and other cell types. Current studies suggest that the inhibitory action of estradiol in the GnRH neuron is at least partly mediated by estrogen receptors expressed in the plasma membrane, rather than those present in the nucleus. SECTION CHIEF Kevin
Catt received the M.B., B.S. (1956) and M.D. (1960) degrees from the
University of Melbourne, Australia. Following clinical and research
training at the Royal Melbourne and Alfred Hospitals, he served as
Registrar and Lecturer at the University Department of Medicine, Royal
Melbourne Hopsital. After completing Ph.D. studies in the Department
of Biochemistry, Monash University, he was Senior Lecturer and subsequently
Reader in Medicine at the Department of Medicine, Monash University.
He joined the NICHD as a Visiting Scientist in 1970, and became the
Chief of Endocrinology and Reproduction Research Branch in 1976. Contact Information Kevin
J. Catt, M.D., Ph.D
Personnel: ·
Albert Baukal, Chemist, Bldg. 49, Rm. 6A-35; tel: 301-496-4067;
email: adu@cu.nih.gov Collaborators: ·
Laszlo Hunyady, M.D., Ph.D., D.Sc., Dept. of Physiology, Semmelweis
University of Medicine, Budapest, Hungary BIBLIOGRAPHY Olivares-Reyes JA, Smith RD, Hunyady L, Shah BH, Catt KJ. (2001). Agonist-induced signaling, desensitization, and internalization of a phosphorylation-deficient at1a angiotensin receptor. J Biol Chem. 276(41):37761-8. pdf Garcia-Caballero A, Olivares-Reyes JA, Catt KJ, Garcia-Sainz JA. (2001) Angiotensin AT(1) receptor phosphorylation and desensitization in a hepatic cell line. Roles of protein kinase c and phosphoinositide 3-kinase. Mol Pharmacol. 59(3):576-85. pdf Gaborik Z, Szaszak M, Szidonya L, Balla B, Paku S, Catt KJ, Clark AJ, Hunyady L. (2001) Beta-arrestin- and dynamin-dependent endocytosis of the AT1 angiotensin receptor. Mol Pharmacol. 59(2):239-47. pdf Olivares-Reyes JA, Jayadev S, Hunyady L, Catt KJ, Smith RD. (2000) Homologous and heterologous phosphorylation of the AT(2) angiotensin receptor by protein kinase C. Mol Pharmacol. 58(5):1156-61. pdf Van Goor F, LeBeau AP, Krsmanovic LZ, Sherman A, Catt KJ, Stojilkovic SS. (2000) Amplitude-dependent spike-broadening and enhanced Ca(2+) signaling in GnRH-secreting neurons. Biophys J. 79(3):1310-23. pdf Zhang M, Zhao X, Chen HC, Catt KJ, Hunyady L. (2000) Activation of the AT1 angiotensin receptor is dependent on adjacent apolar residues in the carboxyl terminus of the third cytoplasmic loop. J Biol Chem. 275(21):15782-8. pdf Van Goor F, Krsmanovic LZ, Catt KJ, Stojilkovic SS. (1999) Coordinate regulation of gonadotropin-releasing hormone neuronal firing patterns by cytosolic calcium and store depletion. Proc Natl Acad Sci U S A. 96(7):4101-6. pdf Krsmanovic LZ, Mores N, Navarro CE, Tomic M, Catt KJ. (2001) Regulation of Ca(2+)-Sensitive Adenylyl Cyclase in Gonadotropin-Releasing Hormone Neurons. Mol. Endocrinol. 15(3):429-440. pdf de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 52(3):415-72. pdf Krsmanovic LZ, Martinez-Fuentes AJ, Arora KK, Mores N, Tomic M, Stojilkovic SS, Catt KJ. (2000) Local regulation of gonadotroph function by pituitary gonadotropin-releasing hormone. Endocrinology. 141(3):1187-95. pdf Chung HO, Yang Q, Catt KJ, Arora KK. (1999) Expression and function of the gonadotropin-releasing hormone receptor are dependent on a conserved apolar amino acid in the third intracellular loop. J Biol Chem. 274(50):35756-62. pdf Arora KK, Chung HO, Catt KJ. (1999) Influence of a species-specific extracellular amino acid on expression and function of the human gonadotropin-releasing hormone receptor. Mol Endocrinol. 13(6):890-6. pdf Krsmanovic LZ, Martinez-Fuentes AJ, Arora KK, Mores N, Navarro CE, Chen HC, Stojilkovic SS, Catt KJ. (1999) Autocrine regulation of gonadotropin-releasing hormone secretion in cultured hypothalamic neurons. Endocrinology. 140(3):1423-31. pdf Smith RD, Hunyady L, Olivares-Reyes JA, Mihalik B, Jayadev S, Catt KJ. (1998) Agonist-induced phosphorylation of the angiotensin AT1a receptor is localized to a serine/threonine-rich region of its cytoplasmic tail. Mol Pharmacol. 1998 54(6):935-41. pdf Krsmanovic LZ, Mores N, Navarro CE, Saeed SA, Arora KK, Catt KJ. (1998) Muscarinic regulation of intracellular signaling and neurosecretion in gonadotropin-releasing hormone neurons. Endocrinology. 139(10):4037-43. pdf Arora KK, Krsmanovic LZ, Mores N, O'Farrell H, Catt KJ. (1998) Mediation of cyclic AMP signaling by the first intracellular loop of the gonadotropin-releasing hormone receptor. J Biol Chem. 273(40):25581-6. pdf Hunyady L, Ji H, Jagadeesh G, Zhang M, Gaborik Z, Mihalik B, Catt KJ. (1998) Dependence of AT1 angiotensin receptor function on adjacent asparagine residues in the seventh transmembrane helix. Mol Pharmacol. 54(2):427-34. pdf Smith RD, Baukal AJ, Zolyomi A, Gaborik Z, Hunyady L, Sun L, Zhang M, Chen HC, Catt KJ. (1998) Agonist-induced phosphorylation of the endogenous AT1 angiotensin receptor in bovine adrenal glomerulosa cells. Mol Endocrinol. 12(5):634-44. pdf Arora KK, Cheng Z, Catt KJ. (1997) Mutations of the conserved DRS motif in the second intracellular loop of the gonadotropin-releasing hormone receptor affect expression, activation, and internalization. Mol Endocrinol. 11(9):1203-12. pdf Balla T, Downing GJ, Jaffe H, Kim S, Zolyomi A, Catt KJ. (1997) Isolation and molecular cloning of wortmannin-sensitive bovine type III phosphatidylinositol 4-kinases. J Biol Chem. 272(29):18358-66. pdf
|
|||
|
Sections & Units in ERRB: Home
Page |
Other helpful links: National
Institute of Child Health & Human Development |
||
