Intracellular inositol 1,4,5-trisphosphate receptors (IP,Rs) form tetrameric Ca2+-release channels that are crucial for Ca2+ signalling in many eukaryotic cells. IP3R subunits contain an N-terminal, cytoplasmic, ligand binding domain linked by a modulatory domain to a channel-forming, hydrophobic C-terminal domain. We assembled and sequenced cDNAs encoding the SI-/SII+/SIII+ splice variant of the human brain type I IP3R, and functionally expressed the full-length receptor, and a C-terminally truncated receptor lacking the final 20% of the protein, in mammalian and insect cells. Both proteins were insoluble, consistent with in vivo immunofluorescence and ligand binding studies. This contrasted with the behaviour of recombinant FKBP12 (a soluble control protein). The truncated receptor also fractionated with the "membrane" pellet after alkaline carbonate treatment. We conclude that the human type I IP3R forms high MW aggregates or complexes in cells when expressed without the C-terminal hydrophobic domain, This behaviour should be considered when expressing and refolding "soluble" human type I IP3R domains for structural studies.