Development of Mimetic peptides for targeted modulation of gap junctions in the cerebral cortex – potential for control of seizures

GM Jacobson, LJ Voss,

We aimed to design and test novel peptides that give blockade of specific subtypes of cell-­‐to-­‐cell connections called gap junctions that we believe to be important in seizure formation. To identify good target regions unique to individual subtypes of gap junction protein, we first performed some simple alignments of sequences for all connexins known to be expressed in the brain, including connexins -­‐32, -­‐36,-­‐ 43 using the software CLUSTALX. This allowed identification of regions that were: a) in an extracellular loop region crucial to formation of functional gap junctions (which we aim to disrupt during their formation) and b) unique to particular gap junction proteins of interest, such as connexin36. We were able to identify a number of mimetic peptides that we believe are likely to give moderately stringent and highly specific blockade of Cx36 gap junction channels (table 1: numbers 3, 5, 7 and 9). Alongside these peptides we also planned to test peptides that other groups had found to be effective blockers of connexin43 based gap junction channels (table 1: number 1). We used a scrambled sequence matched control for each targeting peptide (indicated as: “sequence name”_scrambled) in table 1.

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