Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-04-03
2001-12-18
Allen, Marianne P. (Department: 1631)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007200, C435S007210
Reexamination Certificate
active
06331401
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application various publications are referred to by partial citations within parenthesis. Full citations for these publications may be found at the end of the specification immediately preceding the claims.
These disclosures, in their entireties, are hereby incorporated by reference into this application.
Molecular cloning efforts have provided primary amino acid sequence and signal transduction data for a large collection of serotonin receptor subtypes. These include five cloned 5-HT
1
-like receptors, three cloned 5-HT
2
receptors, and one 5-HT
3
receptor. The 5-HT
1
subfamily includes: 5-HT
1A
(Fargin, 1988; Kobilka, 1989), 5-HT
1B
/5-HT
1D&bgr;
(Weinshank et al., 1991; Demchyshyn et al., 1992; Jin et al., 1992; Adham et al., 1992; Maroteaux et al., 1992; Voight et al., 1991), 5-HT
1D&agr;
(Branchek et al. 1991; Hamblin and Metcalf, 1991; Weinshank et al., 1992), 5-HT
1E
(Levy et al., 1992; McAllister et al., 1992; Zgombick et al., 1992) and 5-HT
1F
(Adham et al., 1993). All five have been shown to couple to the inhibition of adenylate cyclase activity. The 5-HT
2
family includes the 5-HT
2
receptor (Pritchett et al., 1988), 5-HT
1C
(Julius et al., 1989) and 5-HT
2F
(Rat Stomach Fundus; Foquet et al., 1992; Kursar et al., 1992). These receptors all couple to phosphoinositide hydrolysis. The 5-HT
3
receptor is a ligand-gated ion channel (Maricq et al., 1991).
Although this work represents enormous success, the absence of molecular biological information on the 5-HT
4
receptors, which have been shown in native tissues to couple to the activation of adenylate cyclase as a primary mode of signal transduction (Dumius et al., 1988; Bockaert et al., 1990), is apparent. In a previous copending application (U.S. Ser. No., 971,690, filed Nov. 3, 1992), we reported the cloning of the first mammalian 5-HT receptor that couples to the stimulation of adenylate cyclase activity which we named 5-HT
4B
. The 5-HT
4B
receptor was subsequently renamed to the “5-HT
7
receptor” by the “Serotonin Receptor Nomenclature Committee” of the IUPHAR. The pharmacological properties of this receptor indicated that it was similar to a series of functionally defined 5-HT receptors described in the porcine vena cava (Trevethick et al., 1984), cat saphenous vein, coronary arteries (Cushing and Cohen, 1992), and several vascular dilatory effects (Mylecharane and Phillips, 1989). However, the classically defined 5-HT
4
receptor remained to be cloned. We now report the cloning of the pharmacologically-defined 5-HT
4
receptor which we have previously called 5-HT
4A
and now designate as the 5-HT
4
receptor. This receptor also stimulates adenylate cyclase activity but unlike 5-HT
4B
, is sensitive to a series of benzamide derivatives which act as agonists or partial agonists at this subtype. The presence of this subtype in the brain, particularly in areas such as the hippocampus, indicates a potential role in cognitive enhancement. In addition, the 5-HT
4
receptor has been described functionally in the heart, adrenal, bladder, and alimentary canal indicating potential roles in achalasia, hiatal hernia, esophageal spasm, irritable bowel disease, postoperative ileus, diabetic gastroparesis, emesis and other diseases of the gastrointestinal tract, as well as in cardiac, urinary, and endocrine function.
SUMMARY OF THE INVENTION
This invention provides an isolated nucleic acid molecule encoding a mammalian 5-HT
4
receptor. In a preferred embodiment of this invention, the isolated nucleic acid encodes a human 5-HT
4
receptor. In another embodiment of this invention, the nucleic acid molecule encoding a human 5-HT
4
receptor comprises a plasmid designated pBluescript-hS10 (ATCC Accession No. 75392). In another embodiment of this invention a nucleic acid molecule encoding a mammalian 5-HT
4
receptor comprises a plasmid designated pcEXV-S10-87 (ATCC Accession No. 75390). In another embodiment of this invention a nucleic acid molecule encoding a mammalian 5-HT
4
receptor comprises a plasmid designated pcEXV-S10-95 (ATCC Accession No. 75391).
This invention provides a nucleic acid probe comprising a nucleic acid molecule of at least 15 nucleotides capable of specifically hybridizing with a unique sequence included within the sequence of a nucleic acid molecule encoding a mammalian 5-HT
4
receptor. This invention also provides a nucleic acid molecule of at least 15 nucleotides capable of specifically hybridizing with a sequence included within the sequence of a nucleic acid molecule encoding a human 5-HT
4
receptor.
This invention provides an antisense oligonucleotide having a sequence capable of binding specifically to an mRNA molecule encoding a mammalian 5-HT
4
receptor so as to prevent translation of the mRNA molecule. This invention also provides an antisense oligonucleotide having a sequence capable of binding specifically to an mRNA molecule encoding a human 5-HT
4
receptor so as to prevent translation of the mRNA molecule.
This invention provides a monoclonal antibody directed to a mammalian 5-HT
4
receptor. This invention also provides a monoclonal antibody directed to a human 5-HT
4
receptor.
This invention provides a pharmaceutical composition comprising an amount of a substance effective to alleviate the abnormalities resulting from overexpression of a mammalian 5-HT
4
receptor and a pharmaceutically acceptable carrier. This invention also provides a pharmaceutical composition comprising an amount of a substance effective to alleviate abnormalities resulting from underexpression of mammalian 5-HT
4
receptor and a pharmaceutically acceptable carrier.
This invention provides a pharmaceutical composition comprising an amount of a substance effective to alleviate the abnormalities resulting from overexpression of a human 5-HT
4
receptor and a pharmaceutically acceptable carrier. This invention also provides pharmaceutical composition comprising an amount of a substance effective to alleviate abnormalities resulting from underexpression of a human 5-HT
4
receptor and a pharmaceutically acceptable carrier.
This invention provides a transgenic, nonhuman mammal whose genome comprises DNA encoding a mammalian 5-HT
4
receptor so positioned within such genome as to be transcribed into antisense mRNA complementary to mRNA encoding the mammalian 5-HT
4
receptor and when hybridized to mRNA encoding the mammalian 5-HT
4
receptor, the complementary mRNA reduces the translation of the mRNA encoding the mammalian 5-HT
4
receptor.
This invention also provides a transgenic, nonhuman mammal whose genome comprises DNA encoding a human 5-HT
4
so positioned within such genome as to be transcribed into antisense mRNA complementary to mRNA encoding the human 5-HT
4
and when hybridized to mRNA encoding the human 5-HT
4
, the complementary mRNA reduces the translation of the mRNA encoding the human 5-HT
4
.
This invention provides a transgenic, nonhuman mammal whose genome comprises DNA encoding a mammalian 5-HT
4
receptor so positioned within such genome as to be transcribed into antisense mRNA which is complementary to mRNA encoding the mammalian 5-HT
4
receptor and when hybridized to mRNA encoding the 5-HT
4
receptor, the antisense mRNA thereby prevents the translation of mRNA encoding the 5-HT
4
receptor.
This invention also provides a transgenic, nonhuman mammal whose genome comprises DNA encoding a human 5-HT
4
receptor so positioned within such genome as to be transcribed into antisense mRNA which is complementary to mRNA encoding the human 5-HT
4
receptor and when hybridized to mRNA encoding the human 5-HT
4
receptor, the antisense mRNA thereby prevents the translation of mRNA encoding the human 5-HT
4
receptor.
This invention also provides a method of determining the physiological effects of expressing varying levels of a mammalian 5-HT
4
receptor which comprises producing a transgenic nonhuman animal whose levels of mammalian 5-HT
4
receptor expression are varied by use of an inducible promoter which regulates mammalian 5-HT
4
receptor
Branchek Theresa
Gerald Christophe
Hartig Paul R.
Weinshank Richard L.
Allen Marianne P.
Cooper & Dunham LLP
Synaptic Pharmaceutical Corporation
White John P.
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