G protein coupled receptors and uses thereof

Abstract

The present invention provides GPCR polypeptides and polynucleotides, recombinant materials, and transgenic mice, as well as methods for their production. The polypeptides and polynucleotides are useful, for example, in methods of diagnosis and treatment of diseases and disorders. The invention also provides methods for identifying compounds (e.g., agonists or antagonists) using the GPCR polypeptides and polynucleotides of the invention, and for treating conditions associated with GPCR dysfunction with the GPCR polypeptides, polynucleotides, or identified compounds. The invention also provides diagnostic assays for detecting diseases or disorders associated with inappropriate GPCR activity or levels.

1 .- 103 . (canceled) 
     
     
         104 . A method of treating or preventing a neurological disease or disorder in a patient, said method comprising administering to said patient a first nucleic acid molecule encoding a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 488, 243, 558 or 484, or a variant or fragment thereof. 
     
     
         105 . The method of  claim 104 , wherein said first nucleic acid encodes a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, or a variant or fragment thereof, further comprising administering to said patient a second nucleic acid molecule encoding a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, or a variant or fragment thereof, wherein said first and second nucleic acid molecule encode different GPCR polypeptides. 
     
     
         106 . A method of treating or preventing a neurological disease or disorder in a patient, said method comprising administering to said patient a first compound that modulates the biological activity or expression of a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558 or 484. 
     
     
         107 . The method of  claim 106 , wherein said first compound modulates the biological activity or expression of a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, or a variant or fragment thereof, further comprising administering to said patient a second compound that modulates the biological activity or expression of a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second compounds modulate the biological activity or expression of different GPCR polypeptides. 
     
     
         108 . The method of  claim 106 , wherein said compound is selected from the group consisting of:
 (a) a nucleic acid molecule comprising a portion of a polynucleotide sequence set forth in any one of SEQ ID NOs: 1014, 894, 1049, or 1012 or a complement thereof;   (b) an antibody that specifically binds a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 488, 243, 558 or 484; and   (c) a small molecule.   
     
     
         109 . A method of treating or preventing a metabolic disease or disorder in a patient, said method comprising administering to said patient a first nucleic acid molecule encoding a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, or a variant or fragment thereof. 
     
     
         110 . The method of  claim 109 , further comprising administering to said patient a second nucleic acid molecule encoding a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, or a variant or fragment thereof, wherein said first and second nucleic acid molecules encode different GPCR polypeptides. 
     
     
         111 . A method of treating or preventing a metabolic disease or disorder in a patient, said method comprising administering to said patient a first compound that modulates the biological activity or expression of a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 552, 488, or 243. 
     
     
         112 . The method of  claim 111 , further comprising administering to said patient a second compound that modulates the biological activity or expression of a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second compounds modulate the biological activity or expression of different GPCR polypeptides. 
     
     
         113 . The method of  claim 111 , wherein said compound is selected from the group consisting of:
 (a) a nucleic acid molecule comprising a portion of a polynucleotide sequence set forth in any one of SEQ ID NOs:1046, 1014, or 894 or a complement thereof;   (b) an antibody that specifically binds a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 552, 488, or 243; and   (c) a small molecule.   
     
     
         114 . A method for determining whether a patient has an increased risk for developing a neurological or metabolic disease or disorder, said method comprising determining the presence of a mutation or polymorphism in a first gene encoding a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 552, 488, or 243 in a patient, wherein the presence of said mutation or polymorphism indicates that said patient has an increased risk for developing a neurological or metabolic disease or disorder. 
     
     
         115 . The method of  claim 114 , further comprising determining the presence of a mutation or polymorphism in a second gene encoding a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 552, 488, or 243 in a patient, wherein said first and second genes encode different GPCR polypeptides, and wherein the presence of both mutations or polymorphisms indicates that said patient has an increased risk for developing a neurological or metabolic disease or disorder. 
     
     
         116 . A method for determining whether a patient has an increased risk for developing a neurological or metabolic disease or disorder, said method comprising measuring in said patient or a biological sample obtained from said patient a level of biological activity of a first GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 552, 488, or 243, wherein an altered level in said biological activity, relative to a normal control level, indicates that said patient has an increased risk for developing a neurological or metabolic disease or disorder. 
     
     
         117 . The method of  claim 116 , further comprising measuring in said patient or a biological sample obtained from said patient a level of biological activity of a second GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 552, 488, or 243, wherein said first and second GPCR polypeptides are different, and wherein an altered level in both biological activities, relative to a normal control levels, indicates that said patient has an increased risk for developing a neurological or metabolic disease or disorder. 
     
     
         118 . A method for determining whether a patient has an increased risk for developing a neurological or metabolic disease or disorder, said method comprising measuring in said patient or in a cell from said patient a level of expression of a first GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 552, 488, or 243, wherein an altered level in said expression, relative to a normal control level, indicates that said patient has an increased risk for developing a neurological or metaboloic disease or disorder. 
     
     
         119 . The method of  claim 118 , further comprising measuring in said patient or in a cell from said patient a level of expression of a second GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 552, 488, or 243, wherein said first and second GPCR polypeptides are different and wherein an altered level in the expression of both, relative to normal control levels, indicates that said patient has an increased risk for developing a neurological or metabolic disease or disorder. 
     
     
         120 . A method for determining whether a patient has an increased risk for developing a neurological disease or disorder, said method comprising determining the presence of a mutation or polymorphism in a gene encoding a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 558 or 484 in a patient, wherein the presence of said mutation or polymorphism indicates that said patient has an increased risk for developing a neurological disease or disorder. 
     
     
         121 . A method for determining whether a patient has an increased risk for developing a neurological disease or disorder, said method comprising measuring in said patient or a biological sample obtained from said patient a level of biological activity of a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:558 or 484, wherein an altered level in said biological activity, relative to a normal control level, indicates that said patient has an increased risk for developing a neurological disease or disorder. 
     
     
         122 . A method for determining whether a patient has an increased risk for developing a neurological disease or disorder, said method comprising measuring in said patient or in a cell from said patient the expression of a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:558 or 484, wherein an altered level in said expression, relative to a normal control level, indicates that said patient has an increased risk for developing a neurological disease or disorder. 
     
     
         123 . The method of any one of  claims 118  or  122 , wherein said expression is determined by measuring levels of said GPCR polypeptide or an RNA encoding said GPCR polypeptide. 
     
     
         124 . A method for identifying a compound for the treatment or prevention of a neurological disease or disorder, said method comprising:
 (a) contacting a cell expressing a GPCR polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558 or 484 with a candidate compound; and   (b) measuring a biological activity or expression of said GPCR polypeptide expressed in said cell,   wherein altered biological activity or expression of said GPCR polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound useful for the treatment of a neurological disease or disorder.   
     
     
         125 . A method for identifying a compound for the treatment or prevention of a neurological disease or disorder, said method comprising:
 (a) contacting a GPCR polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558 or 484 with a candidate compound; and   (b) determining whether said candidate compound binds to said GPCR polypeptide, wherein binding of said candidate compound to said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment or prevention of a neurological disease or disorder.   
     
     
         126 . A method for identifying a compound for the treatment of a neurological disease or disorder, said method comprising:
 (a) administering a candidate compound to a transgenic animal expressing a transgene encoding a GPCR polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558 or 484; and   (b) determining whether said candidate compound alters a biological activity or expression of said GPCR polypeptide, wherein an alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a neurological disease or disorder.   
     
     
         127 . A method for identifying a compound for the treatment of a neurological disease or disorder, said method comprising:
 (a) administering a candidate compound to a transgenic animal expressing a transgene encoding a human GPCR polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558 or 484, said animal having a neurological disease or disorder; and   (b) determining whether said candidate compound treats said neurological disease or disorder.   
     
     
         128 . A method for identifying a compound for the treatment of a neurological disease or disorder, said method comprising:
 (a) administering a candidate compound to an animal comprising a mutation in a first gene encoding a polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558 or 484; wherein said animal exhibits one or more symptoms of a neurological disease or disorder, and   (b) determining whether said candidate compound reduces said one or more symptoms, thereby indicating that said candidate compound is useful for the treatment of a neurological disease or disorder.   
     
     
         129 . The method of  claim 128 , wherein said animal comprises a mutation in a first gene encoding a polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in SEQ ID NO:488 or SEQ ID NO:243, and where said animal further comprises a mutation in a second gene encoding a polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second genes are different. 
     
     
         130 . A method for identifying a compound for the treatment or prevention of a metabolic disease or disorder, said method comprising:
 (a) contacting a cell expressing a GPCR polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488 or 243 with a candidate compound; and   (b) measuring the biological activity or expression of said GPCR polypeptide expressed in said cell,   wherein altered biological activity or expression of said GPCR polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound useful for the treatment of a metabolic disease or disorder.   
     
     
         131 . A method for identifying a compound for the treatment or prevention of a metabolic disease or disorder, said method comprising:
 (a) contacting a GPCR polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243 with a candidate compound; and   (b) determining whether said candidate compound binds to said GPCR polypeptide, wherein binding of said candidate compound to said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment or prevention of a metabolic disease or disorder.   
     
     
         132 . A method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising:
 (a) administering a candidate compound to a transgenic animal expressing a transgene encoding a human GPCR polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488 or 243; and   (b) determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein an alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a metabolic disease or disorder.   
     
     
         133 . A method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising:
 (a) administering a candidate compound to a transgenic animal expressing a transgene encoding a human GPCR polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 48 or 243, said animal having a metabolic disease or disorder; and   (b) determining whether said candidate compound treats said metabolic disease or disorder.   
     
     
         134 . A method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising:
 (a) contacting a candidate compound with a cell from a transgenic animal expressing a transgene encoding a human GPCR polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488 or 243; and   (b) determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein an alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a metabolic disease or disorder.   
     
     
         135 . A method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising:
 (a) administering a candidate compound to a animal comprising a mutation in a gene encoding a polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in SEQ ID NOs:552, 488 or 243, said animal having a metabolic disease or disorder; and   (b) determining whether said candidate compound treats said metabolic disease or disorder.   
     
     
         136 . A method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising:
 (a) contacting a candidate compound with a cell from an animal comprising a mutation in a gene encoding a polypeptide substantially identical to a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488 or 243; and   (b) determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein an alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a metabolic disease or disorder.   
     
     
         137 . An animal model of a neurological or metabolic disease or disorder, wherein said animal model is a non-human mammal comprising a mutation in a first gene encoding a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, and wherein said non-human mammal exhibits one or more symptoms of a neurological or metabolic disease or disorder. 
     
     
         138 . The animal model of  claim 137 , further comprising a mutation in a second gene encoding a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second gene are different. 
     
     
         139 . An animal model of a neurological or metabolic disease or disorder, wherein said animal model is a non-human mammal comprising a first transgene encoding a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, and wherein said non-human mammal exhibits one or more symptoms of a neurological or metabolic disease or disorder. 
     
     
         140 . The animal model of  claim 139 , wherein said animal model further comprises a second transgene encoding a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:552, 488 or 243, wherein said first and second transgenes encode different GPCR polypeptides. 
     
     
         141 . An animal model of a neurological disease or disorder, wherein said animal model is a non-human mammal comprising a mutation in a gene encoding a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:558 or 484, and wherein said non-human mammal exhibits one or more symptoms of a neurological disease or disorder. 
     
     
         142 . An animal model of a neurological disease or disorder, wherein said animal model is a non-human mammal comprising a transgene encoding a GPCR polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs:558 or 484, and wherein said non-human mammal exhibits one or more symptoms of a neurological disease or disorder. 
     
     
         143 . A cell isolated from the non-human mammal of any one of  claims 137 ,  139 ,  141 , and  142 . 
     
     
         144 . A kit for determining the presence of a neurological or metabolic disease or disorder in a patient, wherein said kit comprises a first compound that specifically binds to a polynucleotide having the sequence set forth in any one of SEQ ID NOs:1046, 1014, or 894 or specifically binds to a polypeptide having a sequence set forth in any one of SEQ ID NOs:552, 488, or 243. 
     
     
         145 . The kit of  claim 144 , further comprising a second compound that specifically binds to a polynucleotide having a sequence set forth in any one of SEQ ID NOs:1046, 1014, or 894 or specifically binds to a polypeptide having a sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second compounds bind different polypeptides or polynucleotides. 
     
     
         146 . A kit for determining the presence of a neurological disease or disorder in a patient, wherein said kit comprises a compound that specifically binds to a polynucleotide having a sequence set forth in any one of SEQ ID NOs:1049 or 1012 or specifically binds to a polypeptide having the sequence set forth in any one of SEQ ID NOs:448 or 484.