INTRODUCTION Many agonists that induce increases in the cytosolic Ca 2+ concentration do so by stimulating the production of inositol 1,4,5-trisphosphate (IP 3 ). IP 3 formed at the plasma membrane, diffuses into the cytosol and binds to its receptor located within the membrane of intracellular Ca 2+ stores, resulting in rapid increases in cytosolic Ca 2+ levels [1]. Measurement of the cytosolic Ca 2+ concentra- tion within single cells has revealed remarkable complex- ity in the nature of the Ca 2+ signal [2]. In many cells, agonist stimulation results in repetitive transient increases in the cytosolic Ca 2+ concentration [3]. These Ca 2+ oscillations often originate from a specific subcellu- lar locus [4], and propagate through the cell as Ca 2+ waves [4,5]. In many cases, Ca 2+ signals spread into neighbouring cells, generating intercellular Ca 2+ waves [6]. Indeed, highly organized Ca 2+ signals have been demonstrated in cell monolayers [7], tissue slices [8] and even intact organs [9, 10], and are likely to play an impor- tant role in coordinating the function of these systems. IP 3 receptors are central to the generation of these com- plex Ca 2+ signals and are, therefore, ultimately responsi- ble for the regulation of numerous Ca 2+ -dependent cellular processes. Specific high-affinity binding sites for IP 3 were first identified in bovine adrenal cortex [11] and have subse- quently been reported in a wide variety of other tissues and cell types [12]. The IP 3 receptor has been purified to homogeneity from a variety of sources [13–19] and was first cloned from the cerebellum [20], an abundant source of this protein [21]. IP 3 receptors are in general thought to reside in the endoplasmic reticulum, however, in some tissues, IP 3 receptors have been localized to the plasma membrane [22–24] and nuclei [25–28]. More recent studies have suggested that IP 3 receptors may mediate Ca 2+ release from secretory vesicles ([29], but see [30]) and the golgi apparatus [31]. IP 3 induces Ca 2+ fluxes Research Molecular properties of inositol 1,4,5- trisphosphate receptors S. Patel, 1 S. K. Joseph, 2 A. P. Thomas 1 1 Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA 2 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Summary The receptors for the second messenger inositol 1,4,5-trisphosphate (IP 3 ) constitute a family of Ca 2+ channels responsible for the mobilization of intracellular Ca 2+ stores. Three different gene products (types I–III) have been isolated, encoding polypeptides which assemble as large tetrameric structures. Recent molecular studie advanced our knowledge about the structure, regulation and function of IP 3 receptors. For example, several Ca 2+ - binding sites and a Ca 2+ -calmodulin-binding domain have been mapped within the type I IP 3 receptor, and studies on purified cerebellar IP 3 receptors propose a second Ca 2+ -independent calmodulin-binding domain. In addition, minim requirements for the binding of immunophilins and the formation of tetramers have been identified. Overexpr IP 3 receptors has provided further clues to the regulation of individual IP 3 receptor isoforms present within cells, and the role that they play in the generation of IP 3 -dependent Ca 2+ signals. Inhibition of IP 3 receptor function and expression, and analysis of mutant IP 3 receptors, suggests that IP 3 receptors are involved in such diverse cellular processes as proliferation and apoptosis and are thus, necessary for normal development. Our understanding of the comple and temporal nature of cytosolic Ca 2+ increases and the role that these Ca 2+ signals play in cell function depend upon our knowledge of the structure and the regulation of IP 3 receptors. This review focuses on the molecular properties o these ubiquitous intracellular Ca 2+ channels. 247 Cell Calcium (1999) 25 (3), 247–264 © Harcourt Brace & Co. Ltd 1999 Article No. ceca.1998.0019 Received 2 December 1998 Revised 21 December 1998 Accepted 14 January 1999 Correspondence to : Dr Sandip Patel, Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, Medical Sciences Building, rm H648, 185 South Orange Avenue, Newark, NJ 07103, USA Tel.: +1 (973) 972 1142; fax: +1 (973) 972 7950; e-mail: patels7@umdnj.edu