In this study we have used several complementary techniques to explore the interaction between the membrane linker molecule, ankyrin, and the inositol 1,4,5-trisphosphate (IP) receptor in mouse T-lymphoma cells. Using double immunolabeling and laser confocal microscopy, we have found that both cytoplasmic IP receptor and ankyrin are preferentially accumulated within ligand-induced lymphocyte receptor-capped structures. The binding between ankyrin and IP receptor appears to be very specific. Further analyses indicate that the amino acid sequence GGVGDVLRKPS in the IP receptor shares a great deal of structural homology with the ankyrin-binding domain located in certain well characterized ankyrin-binding proteins such as the cell adhesion molecule, CD44. Biochemical studies using competition binding assays and a synthetic peptide identical to GGVGDVLRKPS (a sequence detected in rat brain IP receptor (amino acids 2548-2558) and mouse brain IP receptor (amino acids 2546-2556)) indicate that this 11-amino acid peptide binds specifically to ankyrin (but not fodrin or spectrin). Furthermore, this peptide competes effectively for ankyrin binding to IP receptor-containing vesicles and/or purified IP receptor, and it blocks ankyrin-induced inhibitory effects on IP binding and IP-mediated internal Ca release in mouse T-lymphoma cells. These findings suggest that this amino acid sequence, GGVGDVLRKPS, which is located close to the C terminus of the IP receptor, resides on the cytoplasmic side (not the luminal side) of IP receptor-containing vesicles. This unique region appears to be an important part of the IP receptor ankyrin-binding domain and may play an important role in the regulation of IP receptor-mediated internal Ca release during lymphocyte activation.

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