p16 MEDIATED REGULATION OF NMDA RECEPTORS

Abstract

Discovered is a novel protein and variants thereof whose activity at the NMDA receptor causes an increased efflux of calcium ions through the channel of said receptor. This activity is downregulated by the NR3A subunit of NMDA. Also discovered are the nucleic acid sequences encoding said novel protein and variants thereof. The discovery is useful for the diagnosing of NMDA receptor dysregulation and the treatment of NMDA receptor dysregulation related disorders. In addition, the discovery is useful for the further discovery of modulators affecting the activity of the novel protein and variants thereof at the NMDA receptor.

1 . An isolated nucleic acid comprising the nucleic acid sequence selected from the group consisting of SEQ ID No. 1, SEQ ID No.: 2, SEQ ID No.: 38, SEQ ID No.: 39, SEQ ID No.: 40, SEQ ID No.: 41, SEQ ID No.: 42, SEQ ID No.: 43, SEQ ID No.: 44, SEQ ID No.: 45, SEQ ID No.: 46, SEQ ID No.: 47, SEQ ID No.: 48, SEQ ID No.: 49, SEQ ID No.: 50, SEQ ID No.: 51, SEQ ID No.: 52, SEQ ID No.: 53, SEQ ID No.: 54, SEQ ID No.: 55, SEQ ID No.: 56, SEQ ID No.: 57, SEQ ID No.: 58, SEQ ID No.: 59, SEQ ID No.: 60, SEQ ID No.: 61, SEQ ID No.: 62, SEQ ID No.: 63, SEQ ID No.: 64, SEQ ID No.: 65, SEQ ID No.: 66, SEQ ID No.: 67, SEQ ID No.: 68, SEQ ID No.: 69, SEQ ID No.: 70, SEQ ID No.: 71, SEQ ID No.: 85, SEQ ID No.: 86, SEQ ID No.: 87, SEQ ID No.: 88, SEQ ID No.: 89 and SEQ ID No.: 90. 
     
     
         2 . The isolated nucleic acid of  claim 1  wherein the nucleic acid is DNA. 
     
     
         3 . An isolated nucleic acid that hybridizes to a nucleic acid selected from the group consisting of SEQ ID No. 1, SEQ ID No.: 2, SEQ ID No.: 38, SEQ ID No.: 39, SEQ ID No.: 40, SEQ ID No.: 41, SEQ ID No.: 42, SEQ ID No.: 43, SEQ ID No.: 44, SEQ ID No.: 45, SEQ ID No.: 46, SEQ ID No.: 47, SEQ ID No.: 48, SEQ ID No.: 49, SEQ ID No.: 50, SEQ ID No.: 51, SEQ ID No.: 52, SEQ ID No.: 53, SEQ ID No.: 54, SEQ ID No.: 55, SEQ ID No.: 56, SEQ ID No.: 57, SEQ ID No.: 58, SEQ ID No.: 59, SEQ ID No.: 60, SEQ ID No.: 61, SEQ ID No.: 62, SEQ ID No.: 63, SEQ ID No.: 64, SEQ ID No.: 65, SEQ ID No.: 66, SEQ ID No.: 67, SEQ ID No.: 68, SEQ ID No.: 69, SEQ ID No.: 70, SEQ ID No.: 71, SEQ ID No.: 85, SEQ ID No.: 86, SEQ ID No.: 87, SEQ ID No.: 88, SEQ ID No.: 89 and SEQ ID No.: 90. 
     
     
         4 . The isolated nucleic acid of  claim 3  wherein there is no more than about a 5% hybridization mismatch. 
     
     
         5 . The isolated nucleic acid of  claim 4  wherein there is no more than about a 2% hybridization mismatch. 
     
     
         6 . The isolated nucleic acid of  claim 5  wherein there is no more than about a 1% hybridization mismatch. 
     
     
         7 . The isolated nucleic acid of  claim 3  wherein the nucleic acid is DNA. 
     
     
         8 . The isolated nucleic acid of  claim 3  wherein the nucleic acid is RNA. 
     
     
         9 . An isolated polypeptide having an amino acid sequence substantially similar to p16, wherein the isolated polypeptide has activity modulating cation efflux through the NMDA receptor. 
     
     
         10 . The isolated polypeptide of  claim 9  wherein the amino acid sequence substantially similar to p16 is an amino acid sequences selected from the group consisting of SEQ ID No.: 3, SEQ ID No.: 4, SEQ ID No.: 5, SEQ ID No.: 6, SEQ ID No.: 7, SEQ ID No.: 8, SEQ ID No.: 9, SEQ ID No.: 10, SEQ ID No.: 11, SEQ ID No.: 12, SEQ ID No.: 13, SEQ ID No.: 14, SEQ ID No.: 15, SEQ ID No.: 16, SEQ ID No.: 17, SEQ ID No.: 18, SEQ ID No.: 19, SEQ ID No.: 20, SEQ ID No.: 21, SEQ ID No.: 22, SEQ ID No.: 23, SEQ ID No.: 24, SEQ ID No.: 25, SEQ ID No.: 26, SEQ ID No.: 27, SEQ ID No.: 28, SEQ ID No.: 29, SEQ ID No.: 30, SEQ ID No.: 31, SEQ ID No.: 32, SEQ ID No.: 33, SEQ ID No.: 34, SEQ ID No.: 35, SEQ ID No.: 36, SEQ ID No.: 37, SEQ ID No.: 91, SEQ ID No.: 92, SEQ ID No.: 93, SEQ ID No.: 94, SEQ ID No.: 95 and SEQ ID No.: 96. 
     
     
         11 . The isolated polypeptide of  claim 9  wherein the amino acid sequence is coded by a nucleotide having a sequence selected from the group consisting of SEQ ID No. 1, SEQ ID No.: 2, SEQ ID No.: 38, SEQ ID No.: 39, SEQ ID No.: 40, SEQ ID No.: 41, SEQ ID No.: 42, SEQ ID No.: 43, SEQ ID No.: 44, SEQ ID No.: 45, SEQ ID No.: 46, SEQ ID No.: 47, SEQ ID No.: 48, SEQ ID No.: 49, SEQ ID No.: 50, SEQ ID No.: 51, SEQ ID No.: 52, SEQ ID No.: 53, SEQ ID No.: 54, SEQ ID No.: 55, SEQ ID No.: 56, SEQ ID No.: 57, SEQ ID No.: 58, SEQ ID No.: 59, SEQ ID No.: 60, SEQ ID No.: 61, SEQ ID No.: 62, SEQ ID No.: 63, SEQ ID No.: 64, SEQ ID No.: 65, SEQ ID No.: 66, SEQ ID No.: 67, SEQ ID No.: 68, SEQ ID No.: 69, SEQ ID No.: 70, SEQ ID No.: 71, SEQ ID No.: 85, SEQ ID No.: 86, SEQ ID No.: 87, SEQ ID No.: 88, SEQ ID No.: 89 and SEQ ID No.: 90. 
     
     
         12 . The isolated polypeptide of  claim 9  wherein the isolated polypeptide forms a homodimer. 
     
     
         13 . The isolated polypeptide of  claim 9  wherein the isolated polypeptide forms an association with PSD-95. 
     
     
         14 . The isolated polypeptide of  claim 9  wherein the isolated polypeptide binds to a class I PDZ domain. 
     
     
         15 . The isolated polypeptide of  claim 14  wherein the isolated polypeptide further comprises an SVK sequence in the c-terminus. 
     
     
         16 . The isolated polypeptide of  claim 9  wherein the isolated polypeptide further comprises a coiled-coil domain. 
     
     
         17 . The isolated polypeptide of claim  20  wherein a first isolated polypeptide is associated with a second isolated polypeptide. 
     
     
         18 . The isolated polypeptide of claim  20  wherein the isolated polypeptide causes an increased efflux of cations through the NMDA receptor. 
     
     
         19 . The isolated polypeptide of  claim 18  wherein the cation efflux activity caused by the isolated polypeptide is negatively regulated by NR3A subunit of the NMDA receptor.