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The Effects of Synthetic ASIC1a Peptide on Glial Proliferation
Author(s) -
Guercio Jennifer C.,
Petroff Elena
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.884.7
Subject(s) - wild type , chemistry , peptide , cell growth , mutant , microbiology and biotechnology , extracellular , potassium channel , charybdotoxin , biochemistry , bk channel , biophysics , biology , membrane potential , gene
Increased activity of large conductance calcium and voltage‐activated potassium (BK) channels has been shown to accelerate glial proliferation. Our previous studies indicate that Acid Sensing Ion channels (ASICs) inhibit BK at physiological pH levels, and that this inhibition can be relieved at acidic pH. Both normal glia and glioma express BK and ASIC channels. We hypothesized that ASIC‐BK interaction at normal pH would inhibit glial growth, and that a drop in extracellular pH would accelerate the cell proliferation through endogenous pH‐dependent regulation of BK channel activity by ASICs. Mouse glia from wild type (wt) and ASIC1 knockout (ko) mice were grown at normal pH 7.4 and in more acidic pH 7.0. Lowering extracellular pH increased glial proliferation in wt. However, the pH‐dependent regulation of glial growth is lost in ASIC1a knockout glia. A BK channel blocker charybdotoxin (CTX) inhibited glial growth at both pH 7.4 and 7.0, in wt and ko. To further examine ASIC1a and glial proliferation, a wild type peptide (with a similar amino acid sequence to ASIC1a's toxin‐like domain) and a mutant peptide (arginine and lysine important for BK inhibition were mutated to alanine) were designed. Cultured wild type glia were grown at pH 7.4 and 7.0, and in both conditions with either the wild type peptide or the mutant peptide. The synthetic wild type peptide treatment showed no significant change in proliferation. However, the glial growth in the presence of the mutant peptide doubled when compared to the control conditions. These results are consistent with the expected competition of the peptides with ASIC for interacting with BK. Since the mutant peptide does has no inhibit BK but presumably interacts with it at the same site as ASIC, it leads to increased BK activity and cell proliferation. This study is a step towards understanding the regulation of glial cell proliferation by ASIC‐BK channel interaction and our long term goal of developing novel approaches to treating gliomas. This work is supported by the R15 NIH grant to E.P.