Type 3 IP3 receptor: Its structure, functions, and related disease implications

Wu, Lvying; Chen, Jin

doi:10.1080/19336950.2023.2267416

Cited by 1 publication

(1 citation statement)

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“…The variant substitutes glutamine to a translation termination codon (p.Q1668X) (XP_038409684), which is predicted to result in a significantly truncated protein (amino acids 1668-2690 missing) if translated. The resulting protein would lack part of the coupling region, the transmembrane region and the C-terminal tail, thus lacking the complete C-terminal channel-pore region (26).…”

Section: Resultsmentioning

confidence: 99%

IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta

Hytönen,

Rönkkö,

Hundi

et al. 2024

Preprint

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Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1,ITPR2andITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in theITPR3gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J). In addition to peripheral neuropathy, immunodeficiency and tooth abnormalities are occasionally present. Here, we report the identification of a homozygous nonsense variant in theITPR3gene in Lancashire Heeler dogs, presenting with a severe developmental enamel defect and reduced nerve conduction velocity. We studied the primary skin fibroblasts of the affected dogs and observed that the nonsense variant inITPR3led to a complete absence of full-length IP3R3 protein. Unexpectedly, the protein levels of IP3R1 and IP3R2 were also markedly decreased, suggesting co-regulation. Functional Ca2+measurements revealed reduced IP3R-mediated Ca2+flux upon stimulation of G-protein-coupled-receptors in the affected dog fibroblasts. We were able to rescue the IP3R1 and IP3R2 depletion by proteasome inhibition but not the IP3R3 loss, which was facilitated by nonsense-mediated mRNA decay. These findings highlight the first spontaneous mammalian phenotype caused by a nonsense variant inITPR3, leading to the loss of IP3R3. The human and canine IP3R3 proteins are highly similar, and our study suggests that the tissue involvement resulting from the receptor’s dysfunction is also conserved. In summary, IP3R3 is critical for enamel formation and peripheral nerve maintenance.Author summaryWe investigated pet dogs, Lancashire Heelers, with impairments in tooth development and in the nerves that regulate limb muscles. Through genetic studies of the dog pedigree, we found that the phenotypes were caused by a recessively inherited mutation in theITPR3gene, which encodes one of three IP3receptors (IP3R) isoforms (IP3R3 isoform) that are needed for intracellular Ca2+signaling. Mutated IP3R3 has been recently linked to a human inherited neuropathy called Charcot-Marie-Tooth disease type 1J, which impairs peripheral nerve function and is accompanied by immunodeficiency and abnormal teeth in some individuals. We showed that in the skin cells of the affected dogs, the full-length IP3R3 protein was completely absent, and also the protein levels of the other two IP3R isoforms (IP3R1 and IP3R2) were severely lowered. This led to impaired agonist-induced Ca2+release and signaling. Our results demonstrate the high conservation between human and canine IP3receptors and their significance for different tissue systems. The genetic studies now highlight that IP3R3 is vital for peripheral nerve function and enamel development.

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Section: Resultsmentioning

confidence: 99%