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Hindered cytoplasmic diffusion of inositol trisphosphate restricts its cellular range of action.

ABSTRACT: The range of action of intracellular messengers is determined by their rates of diffusion and degradation. Previous measurements in oocyte cytoplasmic extracts indicated that the Ca2+-liberating second messenger inositol trisphosphate (IP3) diffuses with a coefficient (~280 ?m2 s-1) similar to that in water, corresponding to a range of action of ~25 ?m. Consequently, IP3 is generally considered a "global" cellular messenger. We reexamined this issue by measuring local IP3-evoked Ca2+ puffs to monitor IP3 diffusing from spot photorelease in neuroblastoma cells. Fitting these data by numerical simulations yielded a diffusion coefficient (?10 ?m2 s-1) about 30-fold slower than that previously reported. We propose that diffusion of IP3 in mammalian cells is hindered by binding to immobile, functionally inactive receptors that were diluted in oocyte extracts. The predicted range of action of IP3 (<5 ?m) is thus smaller than the size of typical mammalian cells, indicating that IP3 should better be considered as a local rather than a global cellular messenger.

SUBMITTER: Dickinson GD

PROVIDER: S-EPMC5516629 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Hindered cytoplasmic diffusion of inositol trisphosphate restricts its cellular range of action.

Dickinson George D GD Ellefsen Kyle L KL Dawson Silvina Ponce SP Pearson John E JE Parker Ian I

Science signaling 20161108 453

The range of action of intracellular messengers is determined by their rates of diffusion and degradation. Previous measurements in oocyte cytoplasmic extracts indicated that the Ca2+-liberating second messenger inositol trisphosphate (IP3) diffuses with a coefficient (~280 μm2 s-1) similar to that in water, corresponding to a range of action of ~25 μm. Consequently, IP3 is generally considered a "global" cellular messenger. We reexamined th ...[more]

PMID: 27919026

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Project description:RationaleThe mechanisms underlying atrial fibrillation (AF), the most common clinical arrhythmia, are poorly understood. Nucleoplasmic Ca2+ regulates gene expression, but the nature and significance of nuclear Ca2+-changes in AF are largely unknown.ObjectiveTo elucidate mechanisms by which AF alters atrial-cardiomyocyte nuclear Ca2+ ([Ca2+]Nuc) and CaMKII (Ca2+/calmodulin-dependent protein kinase-II)-related signaling.Methods and resultsAtrial cardiomyocytes were isolated from control and AF dogs (kept in AF by atrial tachypacing [600 bpm × 1 week]). [Ca2+]Nuc and cytosolic [Ca2+] ([Ca2+]Cyto) were recorded via confocal microscopy. Diastolic [Ca2+]Nuc was greater than [Ca2+]Cyto under control conditions, while resting [Ca2+]Nuc was similar to [Ca2+]Cyto; both diastolic and resting [Ca2+]Nuc increased with AF. IP3R (Inositol-trisphosphate receptor) stimulation produced larger [Ca2+]Nuc increases in AF versus control cardiomyocytes, and IP3R-blockade suppressed the AF-related [Ca2+]Nuc differences. AF upregulated nuclear protein expression of IP3R1 (IP3R-type 1) and of phosphorylated CaMKII (immunohistochemistry and immunoblot) while decreasing the nuclear/cytosolic expression ratio for HDAC4 (histone deacetylase type-4). Isolated atrial cardiomyocytes tachypaced at 3 Hz for 24 hours mimicked AF-type [Ca2+]Nuc changes and L-type calcium current decreases versus 1-Hz-paced cardiomyocytes; these changes were prevented by IP3R knockdown with short-interfering RNA directed against IP3R1. Nuclear/cytosolic HDAC4 expression ratio was decreased by 3-Hz pacing, while nuclear CaMKII phosphorylation was increased. Either CaMKII-inhibition (by autocamtide-2-related peptide) or IP3R-knockdown prevented the CaMKII-hyperphosphorylation and nuclear-to-cytosolic HDAC4 shift caused by 3-Hz pacing. In human atrial cardiomyocytes from AF patients, nuclear IP3R1-expression was significantly increased, with decreased nuclear/nonnuclear HDAC4 ratio. MicroRNA-26a was predicted to target ITPR1 (confirmed by luciferase assay) and was downregulated in AF atrial cardiomyocytes; microRNA-26a silencing reproduced AF-induced IP3R1 upregulation and nuclear diastolic Ca2+-loading.ConclusionsAF increases atrial-cardiomyocyte nucleoplasmic [Ca2+] by IP3R1-upregulation involving miR-26a, leading to enhanced IP3R1-CaMKII-HDAC4 signaling and L-type calcium current downregulation. Graphic Abstract: A graphic abstract is available for this article.

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Hindered cytoplasmic diffusion of inositol trisphosphate restricts its cellular range of action.

Publications

Hindered cytoplasmic diffusion of inositol trisphosphate restricts its cellular range of action.

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