DNA encoding human alpha 1 adrenergic receptors and uses thereof

Abstract

This invention provides an isolated nucleic acid, vectors, transformed mammalian cells and non-human transgenic animals that encode and express normal or mutant alpha 1a, alpha 1b and alpha 1c adrenergic receptor genes. This invention also provides a protein, and an antibody directed to the protein and pharmaceutical compounds related to alpha 1a, alpha 1b and alpha 1c adrenergic receptors. This invention provides nucleic acid probes, and antisense oligonucleotides complementary to alpha 1a, alpha 1b and alpha 1c adrenergic receptor genes. This invention further provides methods for determining ligand binding, detecting expression, drug screening, and treatments for alleviating abnormalities associated with human alpha 1a, alpha 1b and alpha 1c adrenergic receptors.

What is claimed:  
     
         1 . An isolated nucleic molecule encoding a human α 1  adrenergic receptor.  
     
     
         2 . A nucleic acid molecule of  claim 1 , wherein the nucleic acid molecule encodes a human α 1a  adrenergic receptor.  
     
     
         3 . A nucleic acid molecule of  claim 1 , wherein the nucleic acid molecule encodes a human α 1b  adrenergic receptor.  
     
     
         4 . A nucleic acid molecule of  claim 1 , wherein the nucleic acid encodes a human α 1c  adrenergic receptor.  
     
     
         5 . A nucleic acid molecule of  claim 1 , wherein the nucleic acid molecule is a DNA molecule.  
     
     
         6 . A DNA molecule of  claim 5 , wherein the DNA molecule is a cDNA molecule.  
     
     
         7 . A nucleic acid molecule of  claim 1 , wherein the nucleic acid molecule has been so mutated that the human α 1  adrenergic receptor encoded by the nucleic acid molecule is incapable of receptor activity.  
     
     
         8 . A nucleic acid molecule of  claim 7 , wherein the nucleic acid molecule is a DNA molecule.  
     
     
         9 . A DNA molecule of  claim 8 , wherein the DNA molecule is a cDNA molecule.  
     
     
         10 . A vector comprising a DNA molecule of  claim 5 .  
     
     
         11 . A plasmid comprising the vector of  claim 10 .  
     
     
         12 . A vector of  claim 10  adapted for expression in a bacterial cell which comprises the regulatory elements necessary for expression of the DNA in a bacterial cell so located relative to the DNA encoding a human α 1  adrenergic receptor as to permit expression thereof.  
     
     
         13 . A vector of  claim 10  adapted for expression in a yeast cell which comprises the regulatory elements necessary for the expression of the DNA in a yeast cell so located relative to the DNA encoding a human α 1  adrenergic receptor as to permit expression thereof.  
     
     
         14 . A vector of  claim 10  adapted for expression in a mammalian cell which comprises the regulatory elements necessary for expression of the DNA in the mammalian cell so located relative to the DNA encoding a human α 1  adrenergic receptor as to permit expression thereof.  
     
     
         15 . A plasmid of  claim 11  adapted for expression in a mammalian cell which comprises the regulatory elements necessary for expression of the DNA in the mammalian cell so located relative to the DNA encoding a human α 1  adrenergic receptor as to permit expression thereof.  
     
     
         16 . A plasmid designated pCEXV-α 1a .  
     
     
         17 . A plasmid designated pcEXV-α 1b .  
     
     
         18 . A plasmid designated pcEXV-α 1c .  
     
     
         19 . A mammalian cell comprising the plasmid of  claim 11 .  
     
     
         20 . A mammalian cell of  claim 19 , wherein the mammalian cell is an LM (tk−) cell.  
     
     
         21 . An LM (tk−) cell comprising the plasmid of  claim 15 .  
     
     
         22 . A nucleic acid probe comprising 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 α 1a  receptor.  
     
     
         23 . A nucleic acid probe comprising 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 α 1b  receptor.  
     
     
         24 . A nucleic acid probe comprising 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 α 1c  receptor.  
     
     
         25 . The nucleic acid probe of  claim 22 ,  23 , or  24 , wherein the nucleic acid is DNA.  
     
     
         26 . A nucleic acid probe of  claim 25 , which comprises degenerate oligonucleotides.  
     
     
         27 . An antisense oligonucleotide having a sequence capable of specifically binding to a mRNA molecule encoding a human α 1a  adrenergic receptor so as to prevent translation of the mRNA molecule.  
     
     
         28 . An antisense oligonucleotide having a sequence capable of specifically binding to a mRNA molecule encoding a human α 1b  adrenergic receptor so as to prevent translation of the mRNA molecule.  
     
     
         29 . An antisense oligonucleotide having a sequence capable of specifically binding to a mRNA molecule encoding a human α 1c  adrenergic receptor so as to prevent translation of the mRNA molecule.  
     
     
         30 . An antisense oligonucleotide having a sequence capable of binding specifically to a cDNA molecule of  claim 6 .  
     
     
         31 . Antisense oligonucleotides comprising degenerate oligonucleotides of an antisense oligonucleotide of claims  27 ,  28 , or  29 .  
     
     
         32 . An antisense oligonucleotides of claims  27 ,  28 , or  29  comprising chemical analogs of nucleotides.  
     
     
         33 . A method for detecting expression of a specific human α 1  adrenergic receptor, which comprises obtaining RNA from cells or tissue, contacting the RNA so obtained with a nucleic acid probe of  claim 22 ,  23  or  24  under hybridizing conditions, detecting the presence of any mRNA hybridized to the probe, the presence of mRNA hybridized to the probe indicating expression of the specific human α 1  adrenergic receptor, and thereby detecting the expression of the specific human a adrenergic receptor.  
     
     
         34 . A method of detecting expression of a specific human α 1  adrenergic receptor in a cell or tissue by in situ hybridization, contacting the cell or tissue with a nucleic acid probe of  claim 25  or an antisense oligonucleotide of claims  27 ,  28  or  29  under hybridizing conditions, detecting the presence of any mRNA hybridized to the probe, the presence of mRNA hybridized to the probe indicating expression of the specific human α 1  adrenergic receptor, and thereby detecting the expression of the specific human α 1  adrenergic receptor.  
     
     
         35 . A method of isolating a gene encoding a receptor by nucleic acid sequence homology using a nucleic acid probe of claims  25  or  26 .  
     
     
         36 . A method of  claim 35 , which comprises using the the polymerase chain reaction to obtain a DNA molecule by nucleic acid sequence homology, the DNA molecule of which is used to isolate a gene encoding a receptor.  
     
     
         37 . A nucleic acid molecule comprising the gene identified by the method of claims  35  or  36 .  
     
     
         38 . A method of isolating DNA of  claim 5 , which comprises growing bacteria transformed with a plasmid comprising the DNA of  claim 5 , lysing the cells and purifying the DNA from the lysed cells.  
     
     
         39 . A nucleic acid molecule of  claim 1 , wherein the nucleic acid has been so mutated within a 5′ transcriptional regulatory element or other stability, processing, transcription, or translation-determining region within the 5′ or 3′ untranslated region of the DNA so as to increase the stability of the mRNA or to enhance the processing, transcription, or translation of the RNA.  
     
     
         40 . A nucleic acid molecule of  claim 1 , wherein the nucleic acid has been so mutated within a 5′ transcriptional regulatory element or other stability, processing, transcription, or translation-determining region within the 5′ or 3′untranslated region of the DNA so as to decrease the stability of the mRNA or to diminish the processing, transcription, or translation of the RNA.  
     
     
         41 . An isolated human α 1  adrenergic receptor protein.  
     
     
         42 . An isolated human α 1  adrenergic receptor protein of  claim 41 , wherein the human α 1  adrenergic receptor protein is the human α 1a  adrenergic receptor protein.  
     
     
         43 . An isolated human α 1  adrenergic receptor protein of  claim 41 , wherein the human α 1  adrenergic receptor protein is the human α 1b  adrenergic receptor protein.  
     
     
         44 . An isolated human α 1  adrenergic receptor protein of  claim 41 , wherein the human α 1  adrenergic receptor protein is the human α 1c  adrenergic receptor protein.  
     
     
         45 . A method of preparing a human α 1  adrenergic receptor protein of  claim 41 , which comprises inducing cells to express the human α 1  adrenergic receptor protein, recovering the human α 1  adrenergic receptor from the resulting cells, and purifying the human α 1  adrenergic receptor so recovered.  
     
     
         46 . A method of preparing a human α 1  adrenergic receptor of  claim 41 , which comprises inserting a nucleic acid molecule encoding the human a adrenergic receptor in a suitable vector, inserting the resulting vector in suitable host cell, recovering the human α 1  adrenergic receptor produced by the resulting cell, and purifying the human α 1  adrenergic receptor so recovered.  
     
     
         47 . An antibody directed to a human α 1a  adrenergic receptor or to a protein fragment of the human α 1a  adrenergic receptor.  
     
     
         48 . An antibody directed to a human α 1b  adrenergic receptor or to a protein fragment of the human α 1b  adrenergic receptor.  
     
     
         49 . An antibody directed to a human α 1c  adrenergic receptor or a protein fragment of the human α 1c  adrenergic receptor.  
     
     
         50 . An antibody of claims  47 ,  48  or  49  wherein the antibody is a monoclonal antibody.  
     
     
         51 . A monoclonal antibody of  claim 50  wherein the antibody is directed to an epitope of a human cell-surface α 1  adrenergic receptor and having an amino acid sequence substantially the same as the amino acid sequence for a cell-surface epitope of the human α 1  adrenergic receptor.  
     
     
         52 . A pharmaceutical composition comprising an amount of a substance effective to alleviate the abnormalities resulting from overexpression of a human α 1a  adrenergic receptor and a pharmaceutically acceptable carrier.  
     
     
         53 . A pharmaceutical composition comprising an amount of a substance effective to alleviate the abnormalities resulting from overexpression of a human α 1b  adrenergic receptor and a pharmaceutically acceptable carrier.  
     
     
         54 . A pharmaceutical composition comprising an amount of a substance effective to alleviate the bnormalities resulting from overexpression of a human α 1c  adrenergic receptor and a pharmaceutically acceptable carrier.  
     
     
         55 . A pharmaceutical composition comprising an amount of a substance effective to alleviate abnormalities resulting from underexpression of a human α 1a  adrenergic receptor and a pharmaceutically acceptable carrier.  
     
     
         56 . A pharmaceutical composition comprising an amount of a substance effective to alleviate abnormalities resulting from underexpression of a human α 1b  adrenergic receptor and a pharmaceutically acceptable carrier.  
     
     
         57 . A pharmaceutical composition comprising an amount of a substance effective to alleviate abnormalities resulting from underexpression of a human α 1c  adrenergic receptor and a pharmaceutically acceptable carrier.  
     
     
         58 . A pharmaceutical composition comprising an effective amount of an oligonucleotide of  claim 27  effective to reduce expression of a human α 1a  adrenergic receptor by passing through a cell membrane and specifically binding with mRNA encoding a human α 1a  adrenergic receptor in the cell so as to prevent its translation and a pharmaceutically acceptable hydrophobic carrier capable of passing through a cell membrane.  
     
     
         59 . A pharmaceutical composition comprising an effective amount of an oligonucleotide of  claim 28  effective to reduce expression of a human α 1b  adrenergic receptor by passing through a cell membrane and specifically binding with mRNA encoding a human α 1b  adrenergic receptor in the cell so as to prevent its translation and a pharmaceutically acceptable hydrophobic carrier.  
     
     
         60 . A pharmaceutical composition comprising an effective amount of an oligonucleotide of  claim 29  effective to reduce expression of a human α 1c  adrenergic receptor by passing through a cell membrane and specifically binding with mRNA encoding a human α 1c  adrenergic receptor in the cell so as to prevent its translation and a pharmaceutically acceptable hydrophobic carrier.  
     
     
         61 . A pharmaceutical composition claims  58 ,  59  or  60 , wherein the nucleotide is coupled to a substance which inactivates mRNA.  
     
     
         62 . A pharmaceutical composition of  claim 61 , wherein the substance which inactivates the mRNA is a ribozyme.  
     
     
         63 . A pharmaceutical composition of  claim 61 , wherein the pharmaceutically acceptable hydrophobic carrier capable of passing through a cell membrane comprises a structure which binds to a transporter specific for a selected cell type and is thereby taken up by the cells of the selected cell type.  
     
     
         64 . A pharmaceutical composition which comprises an amount of the antibody of  claim 47  effective to block binding of naturally occurring substrates to a human α 1a  adrenergic receptor and a pharmaceutically acceptable carrier.  
     
     
         65 . A pharmaceutical composition which comprises an amount of the antibody of  claim 48  effective to block binding of naturally occurring substrates to a human α 1b  adrenergic receptor and a pharmaceutically acceptable carrier.  
     
     
         66 . A pharmaceutical composition which comprises an amount of the antibody of  claim 49  effective to block binding of naturally occurring substrates to a human α 1c  adrenergic receptor and a pharmaceutically acceptable carrier.  
     
     
         67 . A transgenic nonhuman mammal which comprises a nucleic acid molecule of  claim 1 .  
     
     
         68 . A transgenic nonhuman mammal which comprises the DNA molecule of  claim 39 .  
     
     
         69 . A transgenic nonhuman mammal which comprises the nucleic acid molecule of  claim 7 .  
     
     
         70 . A transgenic nonhuman mammal which comprises the DNA molecule of  claim 40 .  
     
     
         71 . A transgenic nonhuman mammal whose genome comprises a nucleic acid molecule of  claim 1  so placed as to be transcribed into antisense mRNA complementary to mRNA encoding a human α 1  adrenergic receptor and which hybridizes to mRNA encoding a human α 1  adrenergic receptor thereby reducing its translation.  
     
     
         72 . The transgenic nonhuman mammal of any of claims  67 ,  68 ,  69 ,  70 , or  71 , wherein the nucleic acid molecule further comprises an inducible promoter.  
     
     
         73 . The transgenic nonhuman mammal of any of claims  67 ,  68 ,  69 ,  70 ,  71 , or  72  wherein the nucleic molecule additionally comprises tissue specific regulatory elements.  
     
     
         74 . The transgenic non-human mammal of any of claims  67 ,  68 ,  69 ,  70 ,  71 ,  72 , or  73 , wherein the transgenic non-human mammal is a mouse.  
     
     
         75 . A method of determining the physiological effects of varying the levels of expression of a specific human α 1  adrenergic receptor which comprises producing a transgenic non-human mammal whose levels of expression of a human α 1  adrenergic receptor can be varied by use of an inducible promoter.  
     
     
         76 . A method of determining the physiological effects of expressing varying levels of a specific human α 1  adrenergic receptor which comprises producing a panel of transgenic non-human mammals each expressing a different amount of a human α 1  adrenergic receptor.  
     
     
         77 . A method of determining whether a ligand not known to be capable of specifically binding to a human α 1  adrenergic receptor can specifically bind to a human α 1  adrenergic receptor, which comprises contacting a mammalian cell comprising a plasmid which further comprises a DNA molecule adapted for expression in a mammalian cell which allows subject cell to express a human α 1  adrenergic receptor on the cell surface with the ligand under conditions permitting binding of ligands known to bind to a human α 1  adrenergic receptor, detecting the presence of any ligand bound to the human α 1  adrenergic receptor, the presence of bound ligand thereby determining the ligand binds to the human α 1  adrenergic receptor, and thereby determining whether the ligand binds to the human α 1  adrenergic receptor.  
     
     
         78 . The method of  claim 77 , wherein the receptor is a human α 1a  adrenergic receptor.  
     
     
         79 . The method of  claim 77 , wherein the receptor is a human α 1b  adrenergic receptor.  
     
     
         80 . The method of  claim 77 , wherein the receptor is a human α 1c  adrenergic receptor.  
     
     
         81 . The method of claims  78 ,  79  or  80  wherein the mammalian cell is a non-neuronal cell.  
     
     
         82 . A method of screening drugs to identify drugs which interact with, and bind to, a human α 1  adrenergic receptor on the surface of a cell, which comprises contacting a mammalian cell which comprises a plasmid adapted for expression in a mammalian cell which further comprises a DNA molecule which expresses a human α 1  adrenergic receptor on the cell surface with a plurality of drugs, determining those drugs which bind to the human α 1a  adrenergic receptor expressed on the cell surface of the mammalian cell, and thereby identifying drugs which interact with, and bind to, the human α 1  adrenergic receptor.  
     
     
         83 . The method of  claim 82 , wherein the receptor is a human α 1a  adrenergic receptor.  
     
     
         84 . The method of  claim 82 , wherein the receptor is a human α 1b  adrenergic receptor.  
     
     
         85 . The method of  claim 82 , wherein the receptor is a human α 1c  adrenergic receptor.  
     
     
         86 . The method of claims  83 ,  84  or  85 , wherein the mammalian cell is a non-neuronal cell.  
     
     
         87 . A method of determining whether a ligand not known to be capable of binding to a human α 1  adrenergic receptor can bind to a human α 1  adrenergic receptor, which comprises preparing a cell extract from mammalian cells, which comprise a plasmid adapted for expression in a mammal, which further comprise a DNA molecule which expresses a human α 1  adrenergic receptor on the cell surface, isolating a membrane fraction from the cell extract, incubating the ligand with the membrane fraction under conditions permitting binding of ligands known to bind to the human α 1  adrenergic receptor, detecting the presence of any bound ligand, and thereby determining whether the ligand binds to the human α 1  adrenergic receptor.  
     
     
         88 . The method of  claim 87 , wherein the human α 1  adrenergic receptor is a human α 1a  adrenergic receptor.  
     
     
         89 . The method of  claim 87 , wherein the human α 1  adrenergic receptor is a human α 1b  adrenergic receptor.  
     
     
         90 . The method of  claim 87 , wherein the human α 1  adrenergic receptor is a human α 1c  adrenergic receptor.  
     
     
         91 . The method of claims  88 ,  89  or  90 , wherein the mammalian cell is a non-neuronal cell.  
     
     
         92 . A method of screening drugs to identify drugs that interact with, and bind to, an α 1  adrenergic receptor, which comprises preparing a cell extract from mammalian cells, which comprise a plasmid adapted for expression in a mammalian cell which further comprise a DNA molecule which expresses a human α 1  adrenergic receptor on the cell surface, isolating a membrane fraction from the cell extract, incubating the membrane fraction with a plurality of drugs, determining those drugs which interact with and bind to the human α 1  adrenergic receptor, and thereby identifying drugs which interact with, and bind to, the human α 1  adrenergic receptor.  
     
     
         93 . The method  claim 92 , wherein the receptor is a human α 1a  adrenergic receptor.  
     
     
         94 . The method of  claim 92 , wherein the receptor is a human α 1b  adrenergic receptor.  
     
     
         95 . The method of  claim 92 , wherein the receptor is a human α 1c  adrenergic receptor.  
     
     
         96 . The method of claims  93 ,  94 , or  95 , wherein the mammalian cell is a non-neuronal cell.  
     
     
         97 . A method of identifying a ligand which interacts with, and activates or blocks the activation of, a a human α 1  adrenergic receptor on the surface of a cell, which comprises contacting a mammalian cell which comprises a plasmid adapted for expression in a mammalian cell which further comprises a DNA molecule which expresses a human α 1  adrenergic receptor on the cell surface with the ligand, determining whether the ligand activates or blocks the activation of the receptor using a bioassay such as second messenger assays, and thereby identifying a ligand which interacts with, and activates or blocks the activation of, a human α 1  adrenergic receptor.  
     
     
         98 . The method of  claim 97 , wherein the human α 1  adrenergic receptor is a human α 1a  adrenergic receptor.  
     
     
         99 . The method of  claim 97 , wherein the human α 1  adrenergic receptor is a human α 1b  adrenergic receptor.  
     
     
         100 . The method of  claim 97 , wherein the human α 1  adrenergic receptor is a human α 1c  adrenergic receptor.  
     
     
         101 . The method of claims  98 ,  99  or  100 , wherein the cell is a non-neuronal cell comprising the cellular components required to produce the second messenger which is being identified.  
     
     
         102 . The method of  claim 97 , wherein the ligand is a drug.  
     
     
         103 . A method for identifying a ligand which is capable of binding to and activating or inhibiting a human α 1  adrenergic receptor, which comprises contacting a mammalian cell, wherein the membrane lipids have been labelled by prior incubation with a labelled myo-inositol phosphate molecule, the mammalian cell comprising a plasmid adapted for expression in a mammalian cell which further comprises a DNA molecule which expresses a human α 1  adrenergic receptor with the ligand and identifying an inositol phosphate metabolite released from the membrane lipid as a result of ligand binding to and activating an α 1  adrenergic receptor.  
     
     
         104 . The method of  claim 103 , wherein the human α 1  adrenergic receptor is a human α 1a  adrenergic receptor.  
     
     
         105 . The method of  claim 103 , wherein the human α 1  adrenergic receptor is a human α 1b  adrenergic receptor.  
     
     
         106 . The method of  claim 103 , wherein the human α 1  adrenergic receptor is a human α 1c  adrenergic receptor.  
     
     
         107 . The method of claims  104 ,  105 , or  106 , wherein the cell is a non-neuronal cell expressing the cellular components required to produce the second messenger which is being identified.  
     
     
         108 . The method of  claim 103  wherein the ligand is a drug.  
     
     
         109 . A method for identifying a ligand that is capable of binding to and activating or inhibiting a human α 1  adrenergic receptor, wherein the binding of ligand to the adrenergic receptor results in a physiological response, which comprises contacting a mammalian cell which comprises a plasmid adapted for expression in a mammalian cell which further comprises a DNA molecule which expresses a human α 1  adrenergic receptor with a calcium sensitive fluorescent indicator, removing the indicator that has not been taken up by the cell, contacting the cells with the ligand and identifying an increase or decrease in intracellular Ca +2  as a result of ligand binding to and activating the receptor.  
     
     
         110 . The method of  claim 109 , wherein the human α 1  adrenergic receptor is a human α 1a  adrenergic receptor.  
     
     
         111 . The method of  claim 109 , wherein the human α 1  adrenergic receptor is a human α 1b  adrenergic receptor.  
     
     
         112 . The method of  claim 109 , wherein the human α 1  adrenergic receptor is a human α 1c  adrenergic receptor.  
     
     
         113 . The method of  claim 110 ,  111  or  112 , wherein the cell is a non-neuronal cell expressing the cellular components required to produce the second messenger which is being identified.  
     
     
         114 . The method of  claim 108 , wherein the ligand is a drug.  
     
     
         115 . A ligand identified by the methods of claims  77 ,  87 ,  97 ,  103  or  109 .  
     
     
         116 . A pharmaceutical composition of a drug identified by the methods of claims  82 ,  92 ,  102 ,  108  or  114 .  
     
     
         117 . A method for detecting the presence of a human α 1  adrenergic receptor on the surface of a cell, which comprises contacting the cell with an antibody of  claim 47 , under conditions that permit binding of the antibody to the receptor, detecting the presence of any of the antibody bound to the cell, and thereby the presence of a human α 1a  adrenergic receptor on the surface of the cell.  
     
     
         118 . A method for detecting the presence of a human α 1b  adrenergic receptor on the surface of a cell, which comprises contacting the cell with an antibody of  claim 48 , under conditions that permit binding of the antibody to the receptor, detecting the presence of any of the antibody bound to the cell, and thereby the presence of a human α 1b  adrenergic receptor on the surface of the cell.  
     
     
         119 . A method for detecting the presence of a human α 1c  adrenergic receptor on the surface of a cell, which comprises contacting the cell with an antibody of  claim 49 , under conditions that permit binding of the antibody to the receptor, detecting the presence of any of the antibody bound to the cell, and thereby the presence of a human α 1c  adrenergic receptor on the surface of the cell.  
     
     
         120 . A method for treating an abnormal condition related to an excess of activity of a human α 1  adrenergic receptor subtype, which comprises administering a patient an amount of a pharmaceutical composition of  claim 116 , effective to reduce α 1  adrenergic activity as a result of naturally occurring substrate binding to and activating a specific α 1  adrenergic receptor.  
     
     
         121 . The method of  claim 120 , wherein the condition is benign prostatic hypertrophy.  
     
     
         122 . The method of  claim 120 , wherein the condition is coronary heart disease.  
     
     
         123 . The method of  claim 120 , wherein the condition is insulin resistance.  
     
     
         124 . The method of  claim 120 , wherein the condition is hypertension.  
     
     
         125 . The method of  claim 120 , wherein the condition is urinary retension.  
     
     
         126 . The method of  claim 120 , wherein the condition is glaucoma.  
     
     
         127 . The method of  claim 120 , wherein the condition is erectile dysfunction.  
     
     
         128 . The method of  claim 120 , wherein the condition is Reynaud's syndrome.  
     
     
         129 . The method of treating abnormalities which are alleviated by an increase in the activity of a specific human α 1  adrenergic receptor, which comprises administering a patient an amount of a pharmaceutical composition of  claim 116 , effective to increase the activity of the specific human α 1  adrenergic receptor thereby alleviating abnormalities resulting from abnormally low receptor activity.  
     
     
         130 . The method of  claim 129 , wherein the condition is urinary incontinence.  
     
     
         131 . The method of  claim 129 , wherein the condition is nasal congestion.  
     
     
         132 . The method of  claim 129 , wherein the condition is hypotension.  
     
     
         133 . A method for diagnosing a predisposition to a disorder associated with the expression of a specific human α 1  adrenergic receptor allele which comprises: 
 a. obtaining DNA from subjects suffering from a disorder;  
 b. performing a restriction digest of the DNA with a panel of restriction enzymes;  
 c. electrophoretically separating the resulting DNA fragments on a sizing gel;  
 d. contacting the gel with a nucleic acid probe of  claim 22 ,  23 , or  24  labelled with a detectable marker;  
 e. detecting the labelled bands which have hybridized to the DNA encoding either an α 1a , α 1b  or α 1c  adrenergic receptor, labelled with the detectable marker to create a unique band pattern specific to the DNA of subjects suffering with the disorder;  
 f. preparing DNA for diagnosis by steps a-e;  
 g. comparing the unique band pattern specific to the DNA of patients suffering from the disorder from step e and DNA 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.  
 
     
     
         134 . The method of  claim 133 , wherein a disorder associated with the expression of a specific human α 1  adrenergic allele is diagnosed.  
     
     
         135 . A method of identifying a substance capable of alleviating the abnormalities resulting from overexpression of a specific human α 1  adrenergic receptor which comprises administering a substance to the transgenic non-human mammal of claims  67 ,  68 ,  72 , or  73 , and determining whether the substance alleviates the physical and behavioral abnormalities displayed by the transgenic nonhuman mammal as a result of overexpression of the human α 1  adrenergic receptor subtype.  
     
     
         136 . A method of identifying a substance capable of alleviating the abnormalities resulting from underexpression of a human α 1  adrenergic receptor subtype, which comprises administering a substance to the transgenic mammal of claims  69  or  70 , and determining whether the substance alleviates the physical and behavioral abnormalities displayed by the transgenic nonhuman mammal as a result of underexpression of a human α 1  adrenergic receptor subtype.  
     
     
         137 . A method of treating abnormalities in a subject, 
 wherein the abnormality is alleviated by the reduced expression of a human α 1  adrenergic receptor subtype which comprises administering to a subject an effective amount of the pharmaceutical composition of claims  52 ,  53 ,  54 ,  58 ,  59 ,  60 ,  64 ,  65 ,  66 ,  115  or  116  effective to reduce expression of the α 1  adrenergic receptor subtype.    
     
     
         138 . A method of treating abnormalities resulting from underexpression of a human α 1  adrenergic receptor which comprises administering to a subject an amount of a pharmaceutical composition of  claim 55 ,  56 ,  57 ,  115 , or  116 , effective to alleviate abnormalities resulting from underexpression of the human α 1  adrenergic receptor.  
     
     
         139 . The method of  claim 120 , wherein the condition is atherosclerosis.  
     
     
         140 . The method of  claim 120 , wherein the condition is cardiac arrythmias.  
     
     
         141 . The method of  claim 120 , wherein the condition is sympathetic dystrophy syndrome.  
     
     
         142 . The method of  claim 126 , wherein the condition is congestive heart failure.