In this study we describe for the human inositol-(1,3,4,5)-tetrakisphosphate (InsP 4 )-binding protein, p42 I P 4 , the cellular distribution and subcellular localization in human brain and in transfected neuronal cells. The cDNA sequence of the human p42 I P 4 containing a single open reading frame yields a peptide of 374 amino acids with a calculated molecular mass of 43.4 kDa with a zinc-finger motif at the N-terminus, followed by two pleckstrin homology (PH) domains. Using a peptide-specific antiserum, p42 I P 4 protein was localized in a majority of neuronal cells of human brain sections. In the hypothalamus a subpopulation of paraventricular and infundibular nucleus neurons were strongly immunoreactive for p42 I P 4 . In cortical areas the protein was predominantly found in large pyramidal cells. Some immunoreactivity for p42 I P 4 was also observed in the pyramidal cells of the hippocampal formation. Functional expression of p42 I P 4 protein in neuronal (NG108-15) and non-neuronal (CHO-K1) cells stably transfected with GFP-p42 I P 4 was shown in all cell fractions (homogenate, cytosol and membranes) by specific [ 3 H]Ins(1,3,4,5)P 4 binding activity, which correlated with p42 I P 4 protein detection by Western blot analysis. Using confocal laser scanning microscopy we showed that in NG108-15 and CHO-K1 cells stably transfected with GFP-p42 I P 4 the full length p42 I P 4 protein was localized in the cytoplasm, at the plasma membrane and in the nucleus. A deletion mutant of p42 I P 4 lacking the zinc finger domain resulted in solely a cytosolic and membrane localization but was not found in the nucleus. Thus we can conclude that human p42 I P 4 shows a region-specific localization in the human brain and the zinc finger motif within the protein is responsible for the localization of the protein in the cell nucleus.