Transgenic animal

Abstract

A transgenic rat containing in its genome a nucleotide sequence encoding a Ga subunit protein, which Ga protein subunit is uncoupled from regulation by Regulators of G-Protein Signaling (RGS) proteins, which Gx subunit protein is eventually the dominant-negative G188S mutant of Gax9, which nucleotide sequence is operatively associated with a neuron-specific expression control sequence, wherein the transgenic rat expresses the GA subunit protein in neural cells resulting in extended D-protein coupled receptor signaling mediated by the Ga subunit protein.

1 - 22 . (canceled) 
     
     
         23 . A transgenic animal containing in its genome a nucleotide sequence encoding a mutant Gα subunit protein, wherein said transgenic animal is not a human, and wherein said mutant Gα subunit protein is uncoupled from regulation by Regulators of G-protein Signaling (RGS) proteins, which nucleotide sequence is operatively associated with a neuron-specific expression control sequence, wherein the transgenic animal expresses the Gα subunit protein in neural cells resulting in extended G-protein coupled receptor signaling mediated by the Gα subunit protein. 
     
     
         24 . The transgenic animal of  claim 23 , wherein said transgenic animal exhibits a phenotype selected from the group consisting of vibration as assessed by global behavior assessment; increased center return time as assessed by an open field test; decreased contextual fear conditioning; decreased food intake; decreased body weight; increased sensitivity to 5-HT2A agonists and 5-HT2C agonists; increased cholinergic signs in response to muscarinic agonists; decreased prepulse inhibition; increased hyperactivity in response to NMDA antagonists; and decreased hyperactivity in response to DA agonists. 
     
     
         25 . The transgenic animal of  claim 23 , wherein a G-protein coupled receptor that demonstrates extended signaling is selected from the group consisting of a muscarinic receptor, a 5-hydroxytryptamine (HT)2A receptor, a 5-HT2C receptor, an N-methyl D-aspartate (NMDA) receptor, and a dopamine (DA) receptor. 
     
     
         26 . The transgenic animal of  claim 23 , wherein said mutant Gα subunit protein comprises an amino acid mutation at a position homologous to glycine at position 188 of murine Gαq or glycine at position 302 of yeast Gpa1. 
     
     
         27 . The transgenic animal of  claim 23 , wherein said mutant Gα subunit protein comprises a glycine to serine mutation. 
     
     
         28 . The transgenic animal of  claim 23 , wherein the mutant Gαq subunit does not interact with RGS proteins. 
     
     
         29 . The transgenic animal of  claim 23 , wherein said Gα subunit protein is a member of a Gα subtype selected from the group consisting of Gαo, Gαi, Gαz, and Gαq. 
     
     
         30 . The transgenic animal of  claim 23 , wherein the mutant Gα subunit protein is a Gαq subunit protein with a dominant-negative mutation. 
     
     
         31 . The transgenic animal of  claim 30 , wherein the Gαq is a mouse Gαq. 
     
     
         32 . The transgenic animal of  claim 31 , wherein the mouse Gαq subunit has glycine 188 substituted with serine (G188S). 
     
     
         33 . The transgenic animal of  claim 32 , wherein the mutant Gαq subunit does not interact with RGS proteins. 
     
     
         34 . The transgenic animal of  claim 23 , wherein the neuron-specific promoter is a Thy 1.2 promoter. 
     
     
         35 . The transgenic animal of  claim 23 , wherein the transgenic animal is a rat. 
     
     
         36 . The transgenic animal of  claim 23 , wherein the transgenic animal is a mouse. 
     
     
         37 . A transgenic animal containing in its genome a nucleotide sequence encoding a mutant Gαq subunit protein, wherein said transgenic animal is not a human, wherein said mutant Gαq subunit protein has glycine 188 substituted with serine (G188S) and wherein said mutant Gαq subunit protein is uncoupled from regulation by Regulators of G-protein Signaling (RGS) proteins, said nucleotide sequence being operatively linked with a neuron-specific expression control sequence, wherein the transgenic animal expresses the Gαq subunit protein in neural cells resulting in extended G-protein coupled receptor signaling mediated by the Gαq subunit protein, and wherein said transgenic animal exhibits a phenotype selected from the group consisting of vibration as assessed by global behavior assessment; increased center return time as assessed by an open field test; decreased contextual fear conditioning; decreased food intake; decreased body weight; increased sensitivity to 5-HT2A agonists and 5-HT2C agonists; increased cholinergic signs in response to muscarinic agonists; decreased prepulse inhibition; increased hyperactivity in response to N-methyl D-aspartate (NMDA) antagonists; and decreased hyperactivity in response to dopamine (DA) agonists, as compared to a wild type control. 
     
     
         38 . The transgenic animal of  claim 37 , wherein a G-protein coupled receptor that demonstrates extended signaling is selected from the group consisting of a muscarinic receptor, a 5-hydroxytryptamine (HT) 2 A receptor, a 5-HT2C receptor, an N-methyl D-aspartate (NMDA) receptor, and a dopamine (DA) receptor. 
     
     
         39 . The transgenic animal of  claim 37 , wherein the mutant Gαq subunit protein comprises a dominant-negative mutation. 
     
     
         40 . The method of  claim 37 , wherein the Gαq is a mouse Gαq. 
     
     
         41 . The transgenic animal of  claim 37 , wherein the transgenic animal is a mouse. 
     
     
         42 . A method for identifying a potential agent that modulates RGS modulation of Gα hydrolysis of GTP, which method comprises comparing a phenotype of a test wild-type animal to which a test compound is administered to a phenotype of the transgenic animal of  claim 23 , wherein the test compound modulates RGS modulation of Gα hydrolysis of GTP when the phenotype of the test animal is similar to the phenotype of the transgenic animal. 
     
     
         43 . A method for identifying the effect of a compound on an animal in which Gα is uncoupled from RGS proteins, which method comprises evaluating the phenotype of a transgenic animal of  claim 23  to which a test compound is administered, wherein a change in phenotype relative to a control transgenic animal to which the compound is not administered indicates the effect of the compound in an animal in which Gα is uncoupled from RGS proteins. 
     
     
         44 . A method for generating a transgenic animal that has extended GPCR signaling, which method comprises introducing a nucleotide sequence encoding a Gα subunit protein into the genome of the animal, which Gα protein subunit is uncoupled from regulation by RGS proteins, which nucleotide sequence is operatively associated with a neuron-specific expression control sequence, whereby the transgenic animal expresses the Gα subunit protein in neural cells resulting in extended GPRC signaling.