Intracellular calcium channels: Inositol-1,4,5-trisphosphate receptors

Abstract

The inositol-1,4,5-trisphosphate receptors (InsP3Rs) are the major intracellular Ca2+-release channels in cells. Activity of InsP3Rs is essential for elementary and global Ca2+ events in the cell. There are three InsP3Rs isoforms that are present in mammalian cells. In this review review we will focus primarily on InsP3R type 1. The InsP3R1 is a predominant isoform in neurons and it is most extensively studied isoform. Combination of biophysical and structural methods revealed key mechanisms of InsP3R function and modulation. Cell biological and biochemical studies lead to identification of a large number of InsP3R-binding proteins. InsP3Rs are involved in the regulation of numerous physiological processes, including learning and memory, proliferation, differentiation, development and cell death. Malfunction of InsP3R1 play a role in a number of neurodegenerative disorders and other disease states. InsP3Rs represent a potentially valuable drug target for treatment of these disorders and for modulating activity of neurons and other cells. Future studies will provide better understanding of physiological functions of InsP3Rs in health and disease.

The ancient roots of calcium signalling evolutionary tree

“…In Paramecium, genomic analysis revealed InsP 3 Rs [93], and a second type of CRC resembling a ryanodine receptor (RyR), defined as RyR-LPs [94], or CRCs with mixed features ( [45,87,95] this special issue). When compared with their mammalian counterparts [96,97] RyR-LPs of Paramecium were remarkably different in size [45]. Two of Paramecium CRCs have been thoroughly characterised at a cellular and functional level, including InsP 3 binding [93] and stimulation with RyR agonists [94].…”

Toward a high-resolution structure of IP3R channel

“…2) as well as by the homo- and hetero-tetrameric assembly of the IP 3 R subunits into functional channels. These gene sub-families correspond to sub-types of Ca 2+ release channels that are primarily defined based on the functional and pharmacological criteria rather than rigorous analysis of structure-function relationships (reviewed in [20,21]). However, IP 3 R protein can be subdivided into four functional regions (Fig.…”

“…Inositol 1,4,5-trisphosphate (IP 3 ) is a second messenger produced through phosphoinositide turnover in response to many extracellular stimuli such as hormones, growth factors, neurotransmitters, neurotrophins, odorants and light [20,21]. The changes in IP 3 R pore structure that allow it to open are initiated by IP 3 binding to the N-terminal IP 3 -binding region (Fig.…”

“…Through functional analysis and co-immunoprecipitation studies, some of these sites for protein-protein interactions were mapped to the primary structure of IP 3 R protein (Fig. 2B) (reviewed in [20,21]). While only a single IP 3 binding site exists on a single IP 3 R subunit, there are multiple Ca 2+ binding sites (Fig.…”

Endoplasmic reticulum stress in insulin resistance and diabetes

“…These two release channels although are quite different in size, they appear to have a common ancestor [22], there are three genes for IP 3 Rs [23] and three other for RyRs. RyR1 is characteristic of skeletal muscle, RyR2 of cardiac muscle and RyR3 was identified as a protein responding to TGF-␤ in mink lung epithelial cells [24] but is constitutively expressed in skeletal muscle, neurons, smooth muscle cells and some other non-excitable cells [25].…”