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Theoretical Biological Switch With a Possible Important Role In Parkinson's Disease, Schizophrenia, Hyposmia and the Onco-Parkinson's Mechanism

Abstract

Antagonists for the Histamine Receptor H2 (HRH2_HUMAN) protein may have some efficacy in reducing levodopa-induced dyskinesia in Parkinson's disease. Using short sequence proteomic analysis on the histamine receptor 2 which involves splitting this protein sequence into smaller fragments of ten amino acids and contrasting (using BLAST) against the human protein database.

Three main motifs were found; with the initial two being named the CW-motif and the NxxxNP-motif, with the adjacent amino acid residues being important. The third motif NPxxY overlays the end of the NxxxNP-motif and may form part of a rhodopsin NPxxY(x)5,6F type motif but in this case, it is a variant form NPxxY(x)6,7F present in many of the serotonin and dopamine receptors found here. Using the variants of NPxxY found in the dopamine and serotonin receptors, as a specific amino acid search-term (non-BLAST), it was found that a high proportion of the proteins returned were olfactory proteins.

This small region of similarity amongst dopamine, serotonin and olfactory receptors might be suggestive of a biological switch which might play an important role in Parkinson's disease, schizophrenia and the onco-Parkinson's effect seen in people with Parkinson's disease (who may have raised or lower risk of developing certain types of cancer).

Foreword to the paper

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Figure 1

Figure1. Showing a graph of the HRH2 BLAST results; x-axis number of proteins returned, y-axis sequences. Out of the 239 results returned; 229 are returned in the NC-sequences on the left-hand side, and 10 returned in the CN-sequences on the right-hand side of the graph. Note the two prominent bars on the NC-sequence (left) side at seq49, returning 76 results; and seq56, returning 38 results. Note: There are instances when BLAST fails to return the same NC-sequence in the database that we know to be there, this is due to the nature of the BLAST program when working on small sequences. This obviously does not include the CN-sequences which are obviously reversed sequences in comparison to NC-sequences in the database. So, the number of hits for the CN sequences are typically very low usually zero, and this perhaps highlights a possible "NC" handedness (as opposed to a "CN" handedness) to the human protein primary sequences. The original graph is available online at Histamine HRH2 receptor protein

Figure1.






The Full Table 1 Results displayed in PDF below, just right click and SAVE AS

Table 1 Showing the 91 proteins returned from seq49, seq50, seq56 and seq57. The shading is related to the first motif (CW-motif); rows coloured light grey are sequences/rows that have no Cysteine (C) the sequences/rows coloured dark grey are sequences that have no Tryptophan (W). Where no results were returned in either of the two sets of results a Not Applicable has been inserted but this does not mean that the motif is not present in the protein only that it was not returned from the BLAST search; possibly due to variation in adjacent residues e.g. Cannabinoid receptor 2 (CNR2_HUMAN) does have the second NxxxNP motif. The rows highlighted in bold are the 23 proteins that have clearly shown up with both motifs without having to investigate further to see if in fact these motifs were present.







Figure 2 - Alignment Image

Figure 2. Multiple sequence alignment of twenty-three of the sequences in Table 1. A central gap had to be introduced to ensure a good alignment at the two key points. In the top left highlighted with the black boxes is the CW-motif and long with a WLPFF-motif. On the top right the NxxxNP and NPxxY motifs, with the NPxxY variants from the top to the bottom of the right-hand side.

Figure 2.  Multiple sequence alignment of twenty-three of the sequences in Table 1


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