Protein–protein interactions in intracellular Ca2+-release channel function

Abstract

Release of Ca2+ ions from intracellular stores can occur via two classes of Ca2+-release channel (CRC) protein, the inositol 1,4, 5-trisphosphate receptors (InsP3Rs) and the ryanodine receptors (RyRs). Multiple isoforms and subtypes of each CRC class display distinct but overlapping distributions within mammalian tissues. InsP3Rs and RyRs interact with a plethora of accessory proteins which modulate the activity of their intrinsic channels. Although many aspects of CRC structure and function have been reviewed in recent years, the properties of proteins with which they interact has not been comprehensively surveyed, despite extensive current research on the roles of these modulators. The aim of this article is to review the regulation of CRC activity by accessory proteins and, wherever possible, to outline the structural details of such interactions. The CRCs are large transmembrane proteins, with the bulk of their structure located cytoplasmically. Intra- and inter-complex protein-protein interactions between these cytoplasmic domains also regulate CRC function. Some accessory proteins modulate channel activity of all CRC subtypes characterized, whereas other have class- or even isoform-specific effects. Certain accessory proteins exert both direct and indirect forms of regulation on CRCs, occasionally with opposing effects. Others are themselves modulated by changes in Ca2+ concentration, thereby participating in feedback mechanisms acting on InsP3R and RyR activity. CRCs are therefore capable of integrating numerous signalling events within a cell by virtue of such protein-protein interactions. Consequently, the functional properties of InsP3Rs and RyRs within particular cells and subcellular domains are 'customized' by the accessory proteins present.

Subcellular distribution of the inositol 1,4,5‐trisphosphate receptors: functional relevance and molecular determinants

“…proteins are known to interact with the IP 3 R (Mackrill, 1999). Most of them have a regulatory role (e.g.…”

Calcium channels in lymphocytes

“…This feed-forward mechanism, known as Ca 2+ -induced Ca 2+ release, can lead to the prolonged propagation of Ca 2+ signals. 16,17 In contrast to InsP 3 Rs, only one isotype of RyR is expressed in lymphocytes, RyR1 in B lymphocytes and RyR3 in T lymphocytes, therefore there is no question of heterotetramer formation. 18±22 The role of RyRs in AgR signalling is beginning to be addressed and appears to differ between B and T cells.…”

Sequence diversification of the FK506‐binding proteins in several different genomes

“…The glycine and tyrosine residues in the triad -AYG-are conserved whereas alanine has Fc 0.857. Trp57 (hFKBP-12a sequence position) which is inside the short a helix [33] and is important for interaction with FK506 (Fc 0.857) is replaced by a phenylalanine residue (Fc 0.143) in two mammalian isoforms of FKBP-12b which are known to bind to the ryanodine receptor II (RCR-II) [52].…”

“…Another classification of FKBPs may be based on their cellular localization. Type 1 FKBPs-12 are localized in the cytosol of different phyla [1,2] but some fraction of them has been found associated with various molecular channels and receptors [52,53]. FKBP-12 is absent in some bacteria, e.g.…”