Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1998-06-22
2002-11-12
Kunz, Gary L. (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C530S326000, C930S010000
Reexamination Certificate
active
06479630
ABSTRACT:
The purinergic P
2U
or nucleotide receptor is an integral part of the plasmalemma of various mammalian cell types. The P
U2
receptor described in this application is most similar to a G-protein coupled surface receptor from rat. These receptors are associated with cells such as neutrophils, endothelial cells, and fibroblasts in the immune, neural, muscular, pulmonary and vascular systems. P
2U
receptors stimulate phosphoinositide metabolism and the release of intracellular Ca
++
in the presence of extracellular nucleotides, particularly UTP or ATP. In macrophages, Mg
++
inhibits the response of P
2U
to ATP (Alonso-Torre S R and A Trautmann (1994) J Biol Chem 268:18640-47); and in lung epithelial cells, stimulation of the P
2U
receptor by nucleotides modulates chloride secretion. P
2
receptors have a very low affinity for adenosine and are not activated by the methylxanthine antagonists, caffeine and theophylline.
The P
2U
receptor is in the P
2
receptor family for which the common structural features have been described: 1) seven hydrophobic domains, 2) consensus N-linked glycosylation sequences near the amino terminus, 3) a number of residues common to G-protein coupled receptors (asn
51
, asp
79
, cys
106
, and cys
183
), and 4) potential phosphorylation sites in the third intracellular and carboxyterminal domains (Parr C E et al (1994) Proc Natl Acad Sci 91:3275-79).
In addition to P
2U
, there are four other P
2
receptor subtypes. The P
2X
receptor mediates smooth muscle response following sympathetic nerve stimulation and contains an intrinsic cation channel. The P
2Y
receptor is found in smooth muscle and vascular tissue where it induces vasodilation in response to nitric oxide. The P
2Z
receptor is found primarily on mast or other immune cells, and when activated by ATP, it appears to cause cell permeabilization. The P
2T
receptor, which is only found on platelets, inhibits adenylate cyclase and stimulates the release of intracellular calcium ions. In contrast, P1 receptors are stimulated by adenosine rather than nucleotides.
The G-protein coupled receptors (T7G) characteristically contain seven hydrophobic domains which span the plasma membrane and form a bundle of antiparallel &agr; helices. These transmembrane segments are designated by roman numerals and account for many of the structural and functional features of the receptor. In most cases, the bundle of helices forms a binding pocket; however, the binding site for bulky molecules includes the extracellular N-terminal segment or one or more of the three extracellular loops. Binding may also alter the receptor's intracellular configuration (Watson S and Arkinstall S (1994) The G-Protein Linked Receptor Facts Book, Academic Press, San Diego, Calif.).
The activated receptor interacts with an intracellular G-protein complex which mediates further intracellular signalling activities, generally the production of second messengers such as cyclic AMP (cAMP), phospholipase C, inositol triphosphate, or ion channel proteins. Coupling to G-proteins involves a variable sequence in the C-terminal 10-20 amino acids of the third internal loop between the transmembrane segments V and VI and the intracellular segment immediately C-terminal to transmembrane segment VII. Interaction with Gq also requires the N-terminal 10-20 amino acids of the third internal
Both structural and functional features of T7Gs allow their classification into five categories: &bgr;-type, muscarinic-type, neurokinin-type, nonneurokinin-type, and miscellaneous (Bolander F F (1994) Molecular Endocrinology, Academic Press, San Diego, Calif.); each of which are discussed below. P
2U
is a &bgr;-type receptor and has structural features shared with &bgr;-adrenergic, &agr;-adrenergic, histamine, dopamine, and serotonin receptors. These receptors have a short N-terminus with two conserved N-glycosylation sites, a moderately short third internal loop, and a long C-terminus containing a Ser/Thr-rich region. All adrenergic receptors elevate cAMP or intracellular calcium.
The novel purinergic receptor which is the subject of this patent application was identified among the cDNAs derived from a placental library. Incyte Clone 179696 is a novel homolog of RNU09402, a G-protein coupled surface receptor from rat (Rice WR et al (1995) Am J Respir Cell Molec Biol 12:27-32). Purinergic receptors of the: placenta are likely found on immune or vascular cells and appear to play an important role in signal transduction and other specialized functions of the placenta as briefly described below.
Placenta
The placenta is a thickened discoid temporary organ that acts as the site of interchange of substances between the maternal and fetal bloodstreams. Such substances include oxygen, nutrients, hormones, excretory products, humoral antibodies (immunoglobulin G, IgG), drugs, viruses, or any other chemical or infectious agent that may be present in the maternal circulation.
The placenta consists of a fetal part derived from the chorion, one of the extraembryonic surrounding membranes of the conceptus and of a maternal part (decidua basalis) derived from the region of endometrium that underlies the implantation site. The placenta is thus the only organ composed of cells derived from two individuals. The boundary between maternal and fetal tissues is marked by extracellular products of necrosis referred to as fibrinoid. The anatomy of the human placenta is discussed in detail in Benirschke and Kaufmann, (1992) Pathology of the Human Placenta, Springer-Verlag, New York City, pp 542-635.
Development
The late blastocyst consists of an inner cell mass that gives rise to the embryo and an outer, single layer of trophoblast cells that encloses the blastocyst cavity. Following implantation, trophoblasts become highly invasive, erode and attach to the secretory endometrium. This invasive process involves matrix-degrading metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), adhesion receptors and their extracellular ligands, and the class I human leukocyte antigen-G (HLA-G) molecule. The invasive process is reviewed in Fisher and Damsky (1993 Semin Cell Biol 4(3):183-188) and in Graham and Lala (1992 Biochem Cell Biol 70:867-874).
Trophoblasts give rise to two layers. The inner layer is composed of individual cells, cytotrophoblasts, which have high proliferative potential. The outer layer is composed of syncytial cells, syncytiotrophoblasts, which invade the endometrium and become surrounded by cavernous spaces (lacunae) filled with maternal blood. Finger-like extensions of the cytotrophoblasts grow into these protrusions and act as primary placental villi. The capillaries found in this tissue are a part of the embryonic circulation. Tufted extensions of part of the chorion or chorionic villi are associated with the decidua basalis and develop into the large, elaborately branched outgrowths of the villous chorion. The syncytiotrophoblasts remain until the end of pregnancy, but by the fifth month of gestation, most of the cytotrophoblasts begin to fuse with the syncytiotrophoblast. The few remaining cytotrophoblasts form a discontinuous basal layer.
Chorion
The chorion or fetal part of the placenta has a chorionic plate at the point where the chorionic villi arise. The finger-like villi extend into the endometrial lacuna which are filled with maternal blood released under pressure from the endometrial spiral arteries. A connective tissue core in which the fetal blood vessels develop is derived from extraembryonic mesenchyme surrounded by syncytiotrophoblast and cytotrophoblast cell layers.
During pregnancy, surface area of the villi increases dramatically. The surfaces of the villi are active in the exchange of substances between fetal and maternal circulatory systems. Receptors within the apical microvilli facilitate transport of glucose, amino acids, and IgG from mother to fetus. The mechanism for IgG movement is similar to that of IgA across epithelia. The transport of various materials, particularly nutrients, by the placenta
Au-Young Janice
Coleman Roger
Guegler Karl J.
Stuart Susan G.
Hayes Robert C
Incyte Genomics
Incyte Genomics, Inc.
Kunz Gary L.
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