Nucleic acid encoding neuropeptide Y/peptide YY (Y2) receptors and uses thereof

Abstract

This invention provides isolated nucleic acid molecules encoding Y2 receptors, an isolated, purified Y2 receptor protein, vectors comprising isolated nucleic acid molecules encoding Y2 receptors, mammalian, insect, bacterial and yeast cells comprising such vectors, antibodies directed to the Y2 receptors, nucleic acid probes useful for detecting nucleic acid encoding Y2 receptors, antisense oligonucleotides complementary to unique sequences of a nucleic acid molecule which encodes a Y2 receptor, pharmaceutical compounds related to the Y2 receptors, and nonhuman transgenic animals which express nucleic acid encoding a normal or mutant Y2 receptor. This invention further provides methods for determining ligand binding, detecting expression, drug screening, and methods of treatment involving Y2 receptors.

What is claimed is:  
     
         1 . An isolated nucleic acid molecule encoding a Y2 receptor.  
     
     
         2 . An isolated nucleic acid molecule of  claim 1 , wherein the nucleic acid molecule is a DNA molecule.  
     
     
         3 . An isolated DNA molecule of  claim 2 , wherein the DNA molecule is a cDNA molecule.  
     
     
         4 . An isolated DNA molecule of  claim 2 , wherein the DNA molecule is a genomic DNA molecule.  
     
     
         5 . An isolated nucleic acid molecule of  claim 1 , wherein the nucleic acid molecule is a RNA molecule.  
     
     
         6 . An isolated nucleic acid molecule of  claim 1  wherein the nucleic acid molecule encodes a human Y2 receptor.  
     
     
         7 . An isolated nucleic acid molecule of  claim 6  wherein the nucleic acid molecule encodes a receptor being characterized by an amino acid sequence in the transmembrane region, which amino acid sequence has 60% homology or higher to the amino acid sequence in the transmembrane region of the human Y2 receptor shown in FIG. 11.  
     
     
         8 . An isolated nucleic acid molecule of  claim 6  wherein the human Y2 receptor has substantially the same amino acid sequence as shown in FIG. 2.  
     
     
         9 . An isolated nucleic acid molecule of  claim 6  wherein the human Y2 receptor has the amino acid sequence as shown in FIG. 2.  
     
     
         10 . An isolated nucleic acid molecule of  claim 1  wherein the nucleic acid molecule encodes a rat Y2 receptor.  
     
     
         11 . An isolated nucleic acid molecule of  claim 10  wherein the rat Y2 receptor has substantially the same amino acid sequence as shown in FIG. 8.  
     
     
         12 . An isolated nucleic acid molecule of  claim 10  wherein the rat Y2 receptor has the amino acid sequence shown in FIG. 8.  
     
     
         13 . An isolated nucleic acid molecule of  claim 10  wherein the rat Y2 receptor has substantially the same amino acid sequence as shown in FIG. 9.  
     
     
         14 . An isolated nucleic acid molecule of  claim 10  wherein the rat Y2 receptor has the amino acid sequence shown in FIG. 9.  
     
     
         15 . An isolated, purified Y2 receptor protein.  
     
     
         16 . A vector comprising the nucleic acid molecule of  claim 1 .  
     
     
         17 . A vector comprising the nucleic acid molecule of  claim 6 .  
     
     
         18 . A vector comprising the nucleic acid molecule of  claim 10 .  
     
     
         19 . A vector of  claim 16  adapted for expression in a bacterial cell which comprises the regulatory elements necessary for expression of the nucleic acid in the bacterial cell operatively linked to the nucleic acid encoding the Y2 receptor as to permit expression thereof.  
     
     
         20 . A vector of  claim 16  adapted for expression in a yeast cell which comprises the regulatory elements necessary for expression of the nucleic acid in the yeast cell operatively linked to the nucleic acid encoding the Y2 receptor as to permit expression thereof.  
     
     
         21 . A vector of  claim 16  adapted for expression in an insect cell which comprises the regulatory elements necessary for expression of the nucleic acid in the insect cell operatively linked to the nucleic acid encoding the Y2 receptor as to permit expression thereof.  
     
     
         22 . A vector of  claim 21  wherein the vector is a baculovirus.  
     
     
         23 . A vector of  claim 16  adapted for expression in a mammalian cell which comprises the regulatory elements necessary for expression of the nucleic acid in the mammalian cell operatively linked to the nucleic acid encoding the Y2 receptor as to permit expression thereof.  
     
     
         24 . A vector of  claim 17  adapted for expression in a mammalian cell which comprises the regulatory elements necessary for expression of the nucleic acid in the mammalian cell operatively linked to the nucleic acid encoding the Y2 receptor as to permit expression thereof.  
     
     
         25 . A vector of  claim 24  wherein the vector is a plasmid.  
     
     
         26 . The plasmid of  claim 25  designated pcEXV-hY2 (ATCC Accession No. 75659).  
     
     
         27 . A vector of  claim 18  adapted for expression in a mammalian cell which comprises the regulatory elements necessary for expression of the nucleic acid in the mammalian cell operatively linked to the nucleic acid encoding the Y2 receptor as to permit expression thereof.  
     
     
         28 . A vector of  claim 27  wherein the vector is a plasmid.  
     
     
         29 . The plasmid of  claim 28  designated pcEXV-rY2a (ATCC Accession No. 97035).  
     
     
         30 . The plasmid of  claim 28  designated pcEXV-rY2b (ATCC Accession No. 97036).  
     
     
         31 . A cell comprising the vector of either of claims  24  or  28 .  
     
     
         32 . The cell of  claim 31  wherein the cell is a mammalian cell.  
     
     
         33 . The cell of  claim 32  wherein the mammalian cell is non-neuronal in origin.  
     
     
         34 . The cell of  claim 33  wherein the mammalian cell non-neuronal in origin is a COS-7 cell.  
     
     
         35 . The cell of  claim 33  wherein the mammalian cell non-neuronal in origin is a NIH-3T3 cell.  
     
     
         36 . A NIH-3T3 cell of  claim 36  designated N-hY2-5 (ATCC Accession No. CRL-11825).  
     
     
         37 . The cell of  claim 33  wherein the mammalian cell non-neuronal in origin is a 293 human embryonic kidney cell.  
     
     
         38 . A 293 human embryonic kidney cell of  claim 37  designated 293-hY2-10 (ATCC Accession No. 11837).  
     
     
         39 . 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 Y2 receptor.  
     
     
         40 . The nucleic acid probe of  claim 39  wherein the nucleic acid is DNA.  
     
     
         41 . The nucleic acid probe of  claim 39  wherein the nucleic acid encodes a human Y2 receptor.  
     
     
         42 . The nucleic acid probe of  claim 39  wherein the nucleic acid encodes a rat Y2 receptor.  
     
     
         43 . An antisense oligonucleotide having a sequence capable of specifically hybridizing to an mRNA molecule encoding a Y2 receptor so as to prevent translation of the mRNA molecule.  
     
     
         44 . An antisense oligonucleotide having a sequence capable of specifically hybridizing to the cDNA molecule of  claim 3 .  
     
     
         45 . An antisense oligonucleotide of either of claims  43  or  44  comprising chemical analogues of nucleotides.  
     
     
         46 . An antibody directed to a Y2 receptor.  
     
     
         47 . An antibody of  claim 46 , wherein the Y2 receptor is a human Y2 receptor.  
     
     
         48 . An antibody of  claim 46  wherein the Y2 receptor is a rat Y2 receptor.  
     
     
         49 . An antibody of  claim 46 , wherein the antibody is a monoclonal antibody.  
     
     
         50 . A monoclonal antibody of  claim 49  directed to an epitope of a Y2 receptor present on the surface of a Y2 receptor expressing cell.  
     
     
         51 . A pharmaceutical composition comprising an amount of the oligonucleotide of  claim 43  effective to decrease activity of a Y2 receptor by passing through a cell membrane and binding specifically with mRNA encoding a Y2 receptor in the cell so as to prevent its translation and a pharmaceutically acceptable carrier capable of passing through a cell membrane.  
     
     
         52 . A pharmaceutical composition of  claim 51 , wherein the oligonucleotide is coupled to a substance which inactivates mRNA.  
     
     
         53 . A pharmaceutical composition of  claim 52 , wherein the substance which inactivates mRNA is a ribozyme.  
     
     
         54 . A pharmaceutical composition of  claim 51 , wherein the pharmaceutically acceptable carrier comprises a structure which binds to a receptor on a cell capable of being taken up by cells after binding to the structure.  
     
     
         55 . A pharmaceutical composition of  claim 54 , wherein the structure of the pharmaceutically acceptable carrier is capable of binding to a receptor which is specific for a selected cell type.  
     
     
         56 . A pharmaceutical composition comprising an amount of the antibody of  claim 46  effective to block binding of a ligand to a Y2 receptor and a pharmaceutically acceptable carrier.  
     
     
         57 . A transgenic nonhuman mammal expressing nucleic acid encoding a Y2 receptor.  
     
     
         58 . A transgenic nonhuman mammal comprising a homologous recombination knockout of the native Y2 receptor.  
     
     
         59 . A transgenic nonhuman mammal whose genome comprises antisense nucleic acid complementary to nucleic acid encoding a Y2 receptor so placed as to be transcribed into antisense mRNA which is complementary to mRNA encoding a Y2 receptor and which hybridizes to mRNA encoding a Y2 receptor thereby reducing its translation.  
     
     
         60 . The transgenic nonhuman mammal of either of claims  57  or  59 , wherein the nucleic acid encoding a Y2 receptor additionally comprises an inducible promoter.  
     
     
         61 . The transgenic nonhuman mammal of either of claims  57  or  59 , wherein the nucleic acid encoding a Y2 receptor additionally comprises tissue specific regulatory elements.  
     
     
         62 . A transgenic nonhuman mammal of any of claims  57 ,  58  or  59 , wherein the transgenic nonhuman mammal is a mouse.  
     
     
         63 . A method for determining whether a ligand can bind specifically to a Y2 receptor which comprises contacting a cell transfected with and expressing nucleic acid encoding the Y2 receptor with the ligand under conditions permitting binding of ligands to such receptor, and detecting the presence of any such ligand bound specifically to the Y2 receptor, thereby determining whether the ligand binds specifically to a Y2 receptor.  
     
     
         64 . A method of  claim 63  wherein the Y2 receptor is a human Y2 receptor.  
     
     
         65 . A method of  claim 63  wherein the Y2 receptor is a rat Y2 receptor.  
     
     
         66 . A method for determining whether a ligand can bind specifically to a Y2 receptor, which comprises contacting a cell transfected with and expressing nucleic acid encoding the Y2 receptor with the ligand under conditions permitting binding of ligands to such receptor, and detecting the presence of any such ligand specifically bound to the Y2 receptor, thereby determining whether the ligand binds specifically to a Y2 receptor, wherein the Y2 receptor is characterized by an amino acid sequence in the transmembrane region, such amino acid sequence having 60% homology or higher to the amino acid sequence in the transmembrane region of the Y2 receptor shown in FIG. 11.  
     
     
         67 . A method of  claim 66  wherein the Y2 receptor is a human Y2 receptor.  
     
     
         68 . A method of  claim 66  wherein the Y2 receptor is a rat Y2 receptor.  
     
     
         69 . A method for determining whether a ligand can bind specifically to a Y2 receptor which comprises preparing a cell extract from cells transfected with and expressing nucleic acid encoding the Y2 receptor, isolating a membrane fraction from the cell extract, contacting the ligand with the membrane fraction under conditions permitting binding of ligands to such receptor, and detecting the presence of any ligand bound to the Y2 receptor, thereby determining whether the compound is capable of specifically binding to a Y2 receptor.  
     
     
         70 . A method of  claim 69  wherein the Y2 receptor is a human Y2 receptor.  
     
     
         71 . A method of  claim 69  wherein the Y2 receptor is a rat Y2 receptor.  
     
     
         72 . A method of any of claims  63 ,  64 ,  65 ,  66 ,  67 ,  68 ,  69 ,  70 , or  71  wherein the ligand is not previously known.  
     
     
         73 . A ligand determined by the method of  claim 72 .  
     
     
         74 . A method for determining whether a ligand is a Y2 receptor agonist which comprises contacting a cell transfected with and expressing nucleic acid encoding the Y2 receptor with the ligand under conditions permitting the activation of a functional Y2 receptor response from the cell, and detecting by means of a bioassay, such as a second messenger assay, an increase in Y2 receptor activity, thereby determining whether the ligand is a Y2 receptor agonist.  
     
     
         75 . A method for determining whether a ligand is a Y2 receptor agonist which comprises preparing a cell extract from cells transfected with and expressing nucleic acid encoding the Y2 receptor, isolating a membrane fraction from the cell extract, contacting the membrane fraction of the extract with the ligand under conditions permitting the activation of a functional Y2 receptor response, and detecting by means of a bioassay, such as a second messenger assay, an increase in Y2 receptor activity, thereby determining whether the ligand is a Y2 receptor agonist.  
     
     
         76 . A method of either of claims  74  or  75  wherein the Y2 receptor is a human Y2 receptor.  
     
     
         77 . A method of either of claims  74  or  75  wherein the Y2 receptor is a rat Y2 receptor.  
     
     
         78 . A method for determining whether a ligand is a Y2 receptor antagonist which comprises contacting a cell transfected with and expressing nucleic acid encoding a Y2 receptor with the ligand in the presence of a known Y2 receptor agonist, such as NPY, under. conditions permitting the activation of a functional Y2 receptor response, and detecting by means of a bioassay, such as a second messenger assay, a decrease in Y2 receptor activity, thereby determining whether the ligand is a Y2 receptor antagonist.  
     
     
         79 . A method for determining whether a ligand is a Y2 receptor antagonist which comprises preparing a cell extract from cells transfected with and expressing nucleic acid encoding the Y2 receptor, isolating a membrane fraction from the cell extract, contacting the membrane fraction of the extract with the ligand in the presence of a known Y2 receptor agonist, such as NPY, under conditions permitting the activation of a functional Y2 receptor response, and detecting by means of a bioassay, such as a second messenger assay, a decrease in Y2 receptor activity, thereby determining whether the ligand is a Y2 receptor antagonist.  
     
     
         80 . A method of either of claims  78  or  79  wherein the Y2 receptor is a human Y2 receptor.  
     
     
         81 . A method of either of claims  78  or  79  wherein the Y2 receptor is a rat Y2 receptor.  
     
     
         82 . A method of any of claims  74 ,  75 ,  78 , or  79  wherein the second messenger assay comprises measurement of intracellular cAMP.  
     
     
         83 . A method of any of claims  74 ,  75 ,  78 , or  79  wherein the second messenger assay comprises measurement of intracellular calcium mobilization.  
     
     
         84 . A method of any of claims  63 ,  64 ,  65 ,  66 ,  67 ,  68 ,  69 ,  70 ,  71 ,  72 ,  73 ,  74 ,  75 ,  76 ,  77 ,  78 ,  79 ,  80 , or  81  wherein the cell is a mammalian cell.  
     
     
         85 . A method of  claim 84  wherein the mammalian cell is nonneuronal in origin.  
     
     
         86 . A method of  claim 85 , wherein the mammalian cell is nonneuronal in origin is a COS-7 cell.  
     
     
         87 . A method of  claim 85 , wherein the mammalian cell nonneuronal in origin is a 293 human embryonic kidney cell.  
     
     
         88 . The cell of  claim 87  designated 293-hY2-10 (ATCC Accession No. 11837).  
     
     
         89 . A method of  claim 85 , wherein the mammalian cell nonneuronal in origin is a LM(tk-) cell.  
     
     
         90 . A method of  claim 85 , wherein the mammalian cell nonneuronal in origin is a NIH-3T3 cell.  
     
     
         91 . A cell of  claim 90  designated N-hY2-5 (ATCC Accession No. CRL-11825).  
     
     
         92 . A ligand detected by the method of any of claims  74 ,  75 ,  76 ,  77 ,  78 ,  79 ,  80 , or  81 .  
     
     
         93 . A ligand of  claim 92  wherein the ligand is not previously known.  
     
     
         94 . A pharmaceutical composition comprising an amount of a Y2 receptor agonist determined by the method of either of claims  74  or  75  effective to activate a Y2 receptor and a pharmaceutically acceptable carrier.  
     
     
         95 . A pharmaceutical composition of  claim 94  wherein the Y2 receptor agonist is not previously known.  
     
     
         96 . A pharmaceutical composition which comprises an amount of a Y2 receptor antagonist determined by the method of either of claims  78  or  79  effective to decrease activity of a Y2 receptor and a pharmaceutically acceptable carrier.  
     
     
         97 . A pharmaceutical composition of  claim 96  wherein the Y2 receptor antagonist is not previously known.  
     
     
         98 . A method of screening drugs to identify drugs which specifically bind to a Y2 receptor on the surface of a cell which comprises contacting a cell transfected with and expressing nucleic acid encoding the Y2 receptor with a plurality of drugs under conditions permitting binding of drugs to the Y2 receptor;, and determining those drugs which bind specifically to the transfected cell, thereby identifying drugs which bind specifically to a Y2 receptor.  
     
     
         99 . A method of screening drugs to identify drugs which bind specifically to a Y2 receptor on the surface of a cell which comprises preparing a cell extract from cells transfected with and expressing nucleic acid encoding the Y2 receptor, isolating a membrane fraction from the cell extract, contacting the membrane fraction with a plurality of drugs under conditions permitting binding of drugs to the Y2 receptor, and determining those drugs which bind specifically to the transfected cell, thereby identifying drugs which bind specifically to a Y2 receptor.  
     
     
         100 . A method of either of claims  98  or  99  wherein the Y2 receptor is a human Y2 receptor.  
     
     
         101 . A method of either of claims  98  or  99  wherein the Y2 receptor is a rat Y2 receptor.  
     
     
         102 . A method of screening drugs to identify drugs which act as agonists of a Y2 receptor which comprises contacting a cell transfected with and expressing nucleic acid encoding the Y2 receptor with a plurality of drugs under conditions permitting the activation of a functional Y2 receptor response, and determining those drugs which activate such receptor using a bioassay, such as a second messenger assay, thereby identifying drugs which act as agonists of a Y2 receptor.  
     
     
         103 . A method of screening drugs to identify drugs which act as agonists of a Y2 receptor which comprises preparing a cell extract from cells transfected with and expressing nucleic acid encoding the Y2 receptor, isolating a membrane fraction from the cell extract, contacting the membrane fraction with a plurality of drugs under conditions permitting the activation of a functional Y2 receptor response, and determining those drugs which activate such receptor using a bioassay, such as a second messenger assay, thereby identifying drugs which act as agonists of a Y2 receptor.  
     
     
         104 . A method of either of claims  102  or  103  wherein the Y2 receptor is a human Y2 receptor.  
     
     
         105 . A method of either of claims  102  or  103  wherein the Y2 receptor is a rat Y2 receptor.  
     
     
         106 . A method of screening drugs to identify drugs which act as antagonists of Y2 receptors which comprises contacting a cell transfected with and expressing nucleic acid encoding a Y2 receptor with a plurality of drugs in the presence of a known Y2 receptor agonist such as NPY under conditions permitting the activation of a functional Y2 receptor response, and determining those drugs which inhibit the activation of the receptor using a bioassay, such as a second messenger assay, thereby identifying drugs which act as antagonists of Y2 receptors.  
     
     
         107 . A method of screening drugs to identify drugs which act as antagonists of Y2 receptors which comprises preparing a cell extract from cells transfected with and expressing nucleic acid encoding the Y2 receptor, isolating a membrane fraction from the cell extract, contacting the membrane fraction with a plurality of drugs in the presence of a known Y2 receptor agonist such as NPY under conditions permitting the activation of a functional Y2 receptor response, and determining those drugs which inhibit the activation of the receptor using a bioassay, such as a second messenger assay, thereby identifying drugs which act as antagonists of Y2 receptors.  
     
     
         108 . A method of either of claims  106  or  107  wherein the Y2 receptor is a human Y2 receptor.  
     
     
         109 . A method of either of claims  106  or  107  wherein the Y2 receptor is a rat Y2 receptor.  
     
     
         110 . A method of any of claims  102 ,  103 ,  106  or  107  wherein the second messenger assay comprises measurement of intracellular cAMP.  
     
     
         111 . A method of any of claims  102 ,  103 ,  106 , or  107  wherein the second messenger assay comprises measurement of intracellular calcium mobilization.  
     
     
         112 . A method of any of claims  98 ,  99 ,  100 ,  101 ,  102 ,  103 ,  104 ,  105 ,  106 ,  107 ,  108 , or  109  wherein the cell is a mammalian cell.  
     
     
         113 . A method of  claim 112  wherein the mammalian cell is nonneuronal in origin.  
     
     
         114 . The method of  claim 113  wherein the mammalian cell nonneuronal in origin is a Cos-7 cell.  
     
     
         115 . The method of  claim 113  wherein the mammalian cell nonneuronal in origin is a 293 human embryonic kidney cell.  
     
     
         116 . The cell of  claim 115  designated 293-hY2-10 (ATCC Accession No. 11837).  
     
     
         117 . The method of  claim 113  wherein the mammalian cell nonneuronal in origin is a LM(tk-) cell.  
     
     
         118 . The method of  claim 113  wherein the mammalian cell nonneuronal in origin is a NIH-3T3 cell.  
     
     
         119 . The cell of  claim 118  designated N-hY2-5 (ATCC Accession No. CRL-11825).  
     
     
         120 . A pharmaceutical composition comprising an effective amount of a drug identified by the method of either of claims  102  or  103  and a pharmaceutically acceptable carrier.  
     
     
         121 . A pharmaceutical composition comprising an effective amount of a drug identified by the method of either of claims  106  or  107  and a pharmaceutically acceptable carrier.  
     
     
         122 . A method of detecting expression of a Y2 receptor by a cell by detecting the presence of mRNA coding for a Y2 receptor which comprises obtaining total mRNA from the cell and contacting the mRNA so obtained with the nucleic acid probe of  claim 39  under hybridizing conditions, and detecting the presence of mRNA hybridized to the probe, thereby detecting the expression of Y2 receptor by the cell.  
     
     
         123 . A method of treating an abnormality in a subject, wherein the abnormality is alleviated by activation of a Y2 receptor which comprises administering to a subject an effective amount of the pharmaceutical composition of either of claims  94  or  120 , thereby treating the abnormality.  
     
     
         124 . A method of treating an abnormality in a subject, wherein the abnormality is alleviated by activation of a Y2 receptor which comprises administering to a subject an effective amount of Y2 receptor agonist determined by any of claims  74 ,  75 ,  102 , or  103 , thereby treating the abnormality.  
     
     
         125 . A method of treating an abnormality in a subject, wherein the abnormality is alleviated by decreasing the activity of a Y2 receptor which comprises administering to a subject an effective amount of the pharmaceutical composition of either of claims  96  or  121 , thereby treating the abnormality.  
     
     
         126 . A method of treating an abnormality in a subject, wherein the abnormality is alleviated by decreasing the activity of a Y2 receptor which comprises administering to the subject an effective amount of a Y2 receptor antagonist determined by the methods of any of claims  78 ,  79 ,  106 , or  107 , thereby treating the abnormality.  
     
     
         127 . The method of either of claims  125  or  126  wherein the abnormality is a cognitive disorder.  
     
     
         128 . The method of either of claims  125  or  126  wherein the abnormality is a gastrointestinal disorder.  
     
     
         129 . The method of either of claims  125  or  126  wherein the abnormality is sleeping disorder.  
     
     
         130 . The method of either of claims  125  or  126  wherein the abnormality is epilepsy.  
     
     
         131 . The method of either claims  125  or  126  wherein the abnormality is hypertension.  
     
     
         132 . The method of either of claims  123  or  124  wherein the abnormality is memory loss.  
     
     
         133 . The method of either of claims  123  or  124  wherein the abnormality is diarrhea.  
     
     
         134 . The method of either of claims  123  or  124  wherein the abnormality is nasal congestion.  
     
     
         135 . The method of either of claims  123  or  124  wherein the abnormality is pain.  
     
     
         136 . A method of treating an abnormality in a subject, wherein the abnormality alleviated by decreasing the activity of a Y2 receptor which comprises administering to the subject an amount of the pharmaceutical composition of  claim 56  effective to block binding of ligands to the Y2 receptor, thereby treating the abnormality.  
     
     
         137 . A method of treating an abnormality in a subject, wherein the abnormality is alleviated by decreasing the activity of a Y2 receptor which comprises administering to the subject an effective amount of the pharmaceutical composition of  claim 51 , thereby treating the abnormality.  
     
     
         138 . The method of either of claims  136  or  137  wherein the abnormality is a cognitive disorder.  
     
     
         139 . The method of either of claims  136  or  137  wherein the abnormality is a gastrointestinal disorder.  
     
     
         140 . The method of either of claims  136  or  137  wherein the abnormality is epilepsy.  
     
     
         141 . The method of either of claims  136  or  137  wherein the abnormality is hypertension.  
     
     
         142 . The method of either of claims  136  or  137  wherein the abnormality is sleeping disorder.  
     
     
         143 . A method of detecting the presence of a Y2 receptor on the surface of a cell which comprises contacting the cell with the antibody of  claim 46  under conditions permitting binding of the antibody to the receptor, and detecting the presence of the antibody bound to the cell, thereby detecting the presence of a Y2 receptor on the surface of the cell.  
     
     
         144 . A method of determining the physiological effects of expressing varying levels of Y2 receptors which comprises producing a transgenic nonhuman mammal of  claim 55  whose levels of human Y2 receptor expression are varied by use of an inducible promoter which regulates Y2 receptor expression.  
     
     
         145 . A method of determining the physiological effects of expressing varying levels of Y2 receptors which comprises producing a panel of transgenic nonhuman mammals of  claim 55  each expressing a different amount of Y2 receptor.  
     
     
         146 . A method for identifying a Y2 receptor antagonist capable of alleviating an abnormality in a subject, wherein the abnormality is alleviated by decreasing the activity of a Y2 receptor which comprises administering the antagonist to a transgenic nonhuman mammal of any of claims  57 ,  58 , or  59  and determining whether the antagonist alleviates the physical and behavioral abnormalities displayed by the transgenic nonhuman mammal as a result of activity of a Y2 receptor, thereby identifying a Y2 antagonist.  
     
     
         147 . An antagonist identified by the method of  claim 146 .  
     
     
         148 . A pharmaceutical composition comprising an effective amount of an antagonist identified by the method of  claim 146  and a pharmaceutically acceptable carrier.  
     
     
         149 . A method for treating an abnormality in a subject wherein the abnormality is alleviated by decreasing the activity of a Y2 receptor which comprises administering to the subject an effective amount of the pharmaceutical composition of  claim 148 , thereby treating the abnormality.  
     
     
         150 . A method for identifying a Y2 receptor agonist capable of alleviating an abnormality wherein the abnormality is alleviated by activation of a Y2 receptor which comprises administering the agonist to the transgenic nonhuman mammal of any of claims  57 ,  58 , or  59  and determining whether the agonist alleviates the physical and behavioral abnormalities displayed by the transgenic nonhuman mammal, thereby identifying a Y4 receptor agonist.  
     
     
         151 . An agonist identified by the method of  claim 150 .  
     
     
         152 . A pharmaceutical composition comprising an effective amount of an agonist identified by the method of  claim 150  and a pharmaceutically acceptable carrier.  
     
     
         153 . A method for treating an abnormality in a subject wherein the abnormality is alleviated by activation of a Y2 receptor which comprises administering to the subject an effective amount of the pharmaceutical composition of  claim 152 , thereby treating the abnormality.  
     
     
         154 . A method for diagnosing a predisposition to a disorder associated with the activity of a specific Y2 receptor allele which comprises: 
 a. obtaining nucleic acid of subjects suffering from the disorder;    b. performing a restriction digest of the nucleic acid with a panel of restriction enzymes;    c. electrophoretically separating the resulting nucleic acid fragments on a sizing gel;    d. contacting the resulting gel with a nucleic acid probe capable of specifically hybridizing to nucleic acid encoding a Y2 receptor and labelled with a detectable marker;    e. detecting labelled bands which have hybridized to the nucleic acid encoding a Y2 receptor labelled with a detectable marker to create a unique band pattern specific to the nucleic acid of subjects suffering from the disorder;    f. preparing nucleic acid obtained for diagnosis by steps a-e; and    g. comparing the unique band pattern specific to the nucleic acid of subjects suffering from the disorder from step e and the nucleic acid obtained for diagnosis from step f to determine whether the patterns are the same or different and to diagnose thereby predisposition to the disorder if the patterns are the same.    
     
     
         155 . The method of  claim 154  wherein a disorder associated with the expression of a specific Y2 receptor allele is diagnosed.  
     
     
         156 . A method of preparing the isolated, purified Y2 receptor of  claim 15  which comprises: 
 a. constructing a vector adapted for expression in a cell which comprises the regulatory elements necessary for the expression of nucleic acid in the cell operatively linked to the nucleic acid encoding a Y2 receptor as to permit expression thereof, wherein the cell is selected from the group consisting of bacterial cells, yeast cells, insect cells and mammalian cells;  
 b. inserting the vector of step (a) in a suitable host cell;  
 c. incubating the cells of step (b) under conditions allowing the expression of a Y2′receptor;  
 d. recovering the receptor so produced;  
 e. purifying the receptor so recovered.