Tracing the Evolutionary History of Inositol, 1, 4, 5-Trisphosphate Receptor: Insights from Analyses ofCapsaspora owczarzakiCa²⁺Release Channel Orthologs

Abstract

Cellular Ca2+ homeostasis is tightly regulated and is pivotal to life. Inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) are the major ion channels that regulate Ca2+ release from intracellular stores. Although these channels have been extensively investigated in multicellular organisms, an appreciation of their evolution and the biology of orthologs in unicellular organisms is largely lacking. Extensive phylogenetic analyses reveal that the IP3R gene superfamily is ancient and diverged into two subfamilies, IP3R-A and IP3R-B/RyR, at the dawn of Opisthokonta. IP3R-B/RyR further diversified into IP3R-B and RyR at the stem of Filozoa. Subsequent evolution and speciation of Holozoa is associated with duplication of IP3R-A and RyR genes, and loss of IP3R-B in the vertebrate lineages. To gain insight into the properties of IP3R important for the challenges of multicellularity, the IP3R-A and IP3R-B family orthologs were cloned from Capsaspora owczarzaki, a close unicellular relative to Metazoa (designated as CO.IP3R-A and CO.IP3R-B). Both proteins were targeted to the endoplasmic reticulum. However, CO.IP3R-A, but strikingly not CO.IP3R-B, bound IP3, exhibited robust Ca2+ release activity and associated with mammalian IP3Rs. These data indicate strongly that CO.IP3R-A as an exemplar of ancestral IP3R-A orthologs forms bona fide IP3-gated channels. Notably, however, CO.IP3R-A appears not to be regulated by Ca2+, ATP or PKA-phosphorylation. Collectively, our findings explore the origin, conservation and diversification of IP3R gene families and provide insight into the functionality of ancestral IP3Rs and the added specialization of these proteins in Metazoa.

Differential regulation of ion channels function by proteolysis

“…IP 3 R are ubiquitous, intracellular Ca 2+ release channels predominantly expressed on the endoplasmic reticulum membrane [3, 7, 43] IP 3 R are capable of regulating a diverse array of cellular activities including, gene expression, cell proliferation, differentiation, migration, muscle contraction, digestive enzyme secretion, and cell death [3, 7, 44–46]. To regulate the diverse activities mentioned above with high specificity and fidelity, IP 3 R activate downstream signaling cascades by generating Ca 2+ signals with distinct spatial and temporal characteristics.…”

CRISPR/Cas9-mediated endogenous C-terminal Tagging of Trypanosoma cruzi Genes Reveals the Acidocalcisome Localization of the Inositol 1,4,5-Trisphosphate Receptor

“…Interestingly, when TbIP 3 R (13) or the IP 3 Rs of Capsaspora owczarzaki (another protist in which biochemical characterization of the channel was done (34)) are expressed in DT40 -3KO cells (chicken lymphocytes in which the three vertebrate IP 3 R have been knocked out), the proteins localize to the ER.…”

Region-specific proteolysis differentially modulates type 2 and type 3 inositol 1,4,5-trisphosphate receptor activity in models of acute pancreatitis

“…What is the role of IP 3 R fragmentation in acute pancreatitis? We used both in vitro and in vivo rodent models with different toxic stimuli to characterize the modification of IP 3 R. Consistently, IP 3 R were fragmented in all tested models, indicating that IP 3 R fragmentation may be a general event occurring in acute pancreatitis. Our studies show that IP 3 R fragmentation likely occurs at an early stage in models of acute pancreatitis.…”

“…Inositol 1,4,5-trisphosphate receptors (IP 3 R) 2 are ubiquitous, intracellular Ca 2ϩ release channels expressed predominantly in endoplasmic reticulum (ER) membranes (1)(2)(3)(4). IP 3 R can encode Ca 2ϩ changes with distinct spatial and temporal char-acteristics, and these signals subsequently play essential roles in controlling a plethora of biological processes (1,2,(5)(6)(7).…”