14723 Receptor, a novel G-protein coupled receptor

Details 14723 Receptor, a novel G-protein coupled receptor 14723 Receptor, a novel G-protein coupled receptor

1999-12-08

2002-09-10

Eyler, Yvonne (Department: 1646)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S007200, C435S007210, C435S069100, C435S252300, C435S320100, C530S350000, C536S023500, C536S024310, C436S501000

Reexamination Certificate

active

06448005

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a newly identified receptor belonging to the superfamily of G-protein-coupled receptors. The invention also relates to polynucleotides encoding the receptor. The invention further relates to methods using the receptor polypeptides and polynucleotides as a target for diagnosis and treatment in receptor-mediated disorders, specifically, cardiovascular diseases, including congestive heart failure. The invention further relates to drug-screening methods using the receptor polypeptides and polynucleotides to identify agonists and antagonists for diagnosis and treatment. The invention further encompasses agonists and antagonists based on the receptor polypeptides and polynucleotides. The invention further relates to procedures for producing the receptor polypeptides and polynucleotides.
BACKGROUND OF THE INVENTION
G-protein Coupled Receptors
G-protein coupled receptors (GPCRS) constitute a major class of proteins responsible for transducing a signal within a cell. GPCRs have three structural domains: an amino terminal extracellular domain, a transmembrane domain containing seven transmembrane segments, three extracellular loops, and three intracellular loops, and a carboxy terminal intracellular domain. Upon binding of a ligand to an extracellular portion of a GPCR, a signal is transduced within the cell that results in a change in a biological or physiological property of the cell. GPCRs, along with G-proteins and effectors (intracellular enzymes and channels modulated by G-proteins), are the components of a modular signaling system that connects the state of intracellular second messengers to extracellular inputs.
GPCR genes and gene-products are potential causative agents of disease (Spiegel et al.,
J. Clin. Invest
. 92:1119-1125 (1993); McKusick et al.,
J. Med. Genet
. 30:1-26 (1993)). Specific defects in the rhodopsin gene and the V2 vasopressin receptor gene have been shown to cause various forms of retinitis pigmentosum (Nathans et al.,
Annu. Rev. Genet
. 26:403-424(1992)), and nephrogenic diabetes insipidus (Holtzman et al.,
Hum. Mol. Genet
. 2:1201-1204 (1993)). These receptors are of critical importance to both the central nervous system and peripheral physiological processes. Evolutionary analyses suggest that the ancestor of these proteins originally developed in concert with complex body plans and nervous systems.
The GPCR protein superfamily can be divided into five families: Family I, receptors typified by rhodopsin and the &bgr;2-adrenergic receptor and currently represented by over 200 unique members (Dohlman et al.,
Annu. Rev. Biochem
. 60:653-688 (1991)); Family II, the parathyroid hormone/calcitonin/secretin receptor family (Juppner et al.,
Science
254:1024-1026 (1991); Lin et al.,
Science
254:1022-1024 (1991)); Family III, the metabotropic glutamate receptor family (Nakanishi,
Science
258 597:603 (1992)); Family IV, the cAMP receptor family, important in the chemotaxis and development of
D. discoideum
(Klein et al.,
Science
241:1467-1472 (1988)); and Family V, the fungal mating pheromone receptors such as STE2 (Kurjan,
Annu. Rev. Biochem
. 61:1097-1129 1992)).
There are also a small number of other proteins which present seven putative hydrophobic segments and appear to be unrelated to GPCRs; they have not been shown to couple to G-proteins. Drosophila expresses a photoreceptor-specific protein, bride of sevenless (boss), a seven-transmembrane-segment protein which has been extensively studied and does not show evidence of being a GPCR (Hart et al.,
Proc. Natl. Acad. Sci. USA
90:5047-5051 (1993)). The gene frizzled (fz) in Drosophila is also thought to be a protein with seven transmembrane segments. Like boss, fz has not been shown to couple to G-proteins (Vinson et al.,
Nature
338:263-264 (1989)).
G proteins represent a family of heterotrimeric proteins composed of &agr;, &bgr; and &ggr; subunits, that bind guanine nucleotides. These proteins are usually linked to cell surface receptors, e.g., receptors containing seven transmembrane segments. Following ligand binding to the GPCR, a conformational change is transmitted to the G protein, which causes the &agr;-subunit to exchange a bound GDP molecule for a GTP molecule and to dissociate from the &bgr;&ggr;-subunits. The GTP-bound form of the &agr;-subunit typically functions as an effector-modulating moiety, leading to the production of second messengers, such as cAMP (e.g., by activation of adenyl cyclase), diacylglycerol or inositol phosphates. Greater than 20 different types of a-subunits are known in humans. These subunits associate with a smaller pool of &bgr; and &ggr; subunits. Examples of mammalian G proteins include Gi, Go, Gq, Gs and Gt. G proteins are described extensively in Lodish et al.,
Molecular Cell Biology
, (Scientific American Books Inc., New York, N.Y., 1995), the contents of which are incorporated herein by reference. GPCRs, G proteins and G protein-linked effector and second messenger systems have been reviewed in
The G
-
Protein Linked Receptor Fact Book
, Watson et al., eds., Academic Press (1994).
GPCRs are a major target for drug action and development. Accordingly, it is valuable to the field of pharmaceutical development to identify and characterize previously unknown GPCRs. The present invention advances the state of the art by providing a previously unidentified human GPCR.
SUMMARY OF THE INVENTION
It is an object of the invention to identify novel GPCRs.
It is a further object of the invention to provide novel GPCR polypeptides that are useful as reagents or targets in receptor assays applicable to treatment and diagnosis of GPCR-mediated disorders.
It is a further object of the invention to provide polynucleotides corresponding to the novel GPCR receptor polypeptides that are useful as targets and reagents in receptor assays applicable to treatment and diagnosis of GPCR-mediated disorders and useful for producing novel receptor polypeptides by recombinant methods.
A specific object of the invention is to identify compounds that act as agonists and antagonists and modulate the expression of the novel receptor.
A further specific object of the invention is to provide compounds that modulate expression of the receptor for treatment and diagnosis of GPCR-related disorders.
The invention is thus based on the identification of a novel GPCR, designated the 14273 receptor.
The invention provides isolated 14273 receptor polypeptides including a polypeptide having the amino acid sequence shown in SEQ ID NO 1 (human) and SEQ ID NO 4 (murine), or the amino acid sequence encoded by the cDNA deposited as ATCC No. PTA-1143 on Jan. 5, 2000 (“the deposited cDNA”).
The invention also provides isolated 14273 receptor nucleic acid molecules having the sequence shown in SEQ ID NO 2 (human) and SEQ ID NO 5 (murine) or in the deposited cDNA.
The invention also provides variant polypeptides having an amino acid sequence that is substantially homologous to the amino acid sequence shown in SEQ ID NO 1 or SEQ ID NO 4 or encoded by the deposited cDNA.
The invention also provides variant nucleic acid sequences that are substantially homologous to the nucleotide sequence shown in SEQ ID NO 2 or SEQ ID NO 5 or in the deposited cDNA.
The invention also provides fragments of the polypeptide shown in SEQ ID NO 1 or SEQ ID NO 4 and nucleotide shown in SEQ ID NO 2 or SEQ ID NO 5, as well as substantantially homologous fragments of the polypeptide or nucleic acid.
The inventors have linked expression of the receptor polynucleotides to cardiovascular disease and specifically to congestive heart failure. The inventors have found that receptor mRNA is induced in hypertrophic human cardiac myocytes and that expression correlates with morphological change. This induction is observed in ischemic and dilated hearts.
Therefore, the invention also provides receptor variants that correlate with the cardiovascular disorders.
Cardiac hypertrophy is the principal response of the heart to overload from any cause including ischemia/reperfusion injury, m

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