The Role of a Brain-specific Splice Variant of Ryanodine Receptor Type 1

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The ryanodine receptor type 1 (RyR1) is capable of homotetrameric assembly to form a Ca²⁺ release channel at intracellular Ca²⁺ storage sites such as endoplasmic reticulum (ER). The mRNA transcript encoding full-length RyR1 is approximately 16kb and is mainly distributed in excitable cells. A 2.4-kb mRNA splice variant from the 3'-terminal region of the RyR1 gene coexists specifically in brain together with the full-length form, although the functions of this brain-specific splice variant remain unclear. To investigate the short form of RyR1 in intracellular Ca²⁺ signaling in brain at the cellular level, we established an experimental system whereby the green fluorescent protein (GFP) -tagged brain-specific variant of RyR1 is coexpressed with the full-length protein in the same cell. Both forms of RyR1 were localized in the ER. Caffeine-induced Ca²⁺-release activities in cells expressing both the brain-specific and full-length RyR1 were reduced compared to cells expressing only the full-length form of RyR1. These results suggested that coexpression of the brain-specific splice variant of RyR1 with its full-length counterpart modulates intracellular Ca²⁺ signaling by acting as a dominant-negative subunit of the Ca²⁺ release channel in a tissue-specific fashion.