Inositol hexakisphosphate increases L‐type Ca2+channel activity by stimulation of adenylyl cyclase (original) (raw)
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Intracellular calcium channels: Inositol-1,4,5-trisphosphate receptors
European Journal of Pharmacology, 2014
The inositol-1,4,5-trisphosphate receptors (InsP 3 Rs) are the major intracellular Ca 2+-release channels in cells. Activity of InsP 3 Rs is essential for elementary and global Ca 2+ events in the cell. There are three InsP 3 Rs isoforms that are present in mammalian cells. In this review review we will focus primarily on InsP 3 R type 1. The InsP 3 R1 is a predominant isoform in neurons and it is most extensively studied isoform. Combination of biophysical and structural methods revealed key mechanisms of InsP 3 R function and modulation. Cell biological and biochemical studies lead to identification of a large number of InsP 3 R-binding proteins. InsP 3 Rs are involved in the regulation of numerous physiological processes, including learning and memory, proliferation, differentiation, development and cell death. Malfunction of InsP 3 R1 play a role in a number of neurodegenerative disorders and other disease states. InsP 3 Rs 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 InsP 3 Rs in health and disease.
Proceedings of the National Academy of Sciences, 1988
We report the stoichiometric phosphorylation of an inositol 1,4,5-trisphosphate receptor-binding protein from rat brain by the cAMP-dependent protein kinase but not by protein kinase C or Ca2+/calmodulin-dependent protein kinase. This phosphorylation event does not markedly alter [3H]inositol 1,4,5-trisphosphate-binding characteristics. However, inositol 1,4,5-trisphosphate is only 10% as potent in releasing 45Ca2I from phosphorylated, as compared with native, cerebellar microsomes. Phosphorylation of the inositol 1,4,5-trisphosphate-binding protein by the cAMP-dependent protein kinase may provide a biochemical substrate for secondmessenger cross talk.
Distribution of the inositol 1,4,5-trisphosphate receptor, P400, in adult rat brain
Journal of comparative neurology, 1993
Activation of inositol-1,4,5-trisphosphate receptors (InsP 3 Rs) and ryanodine receptors (RyRs) can lead to the release of Ca 2+ from intracellular stores and propagating Ca 2+ waves. Previous studies of these proteins in neurons have focused on their distribution in adult tissue, whereas, recent functional studies have examined neural tissue extracted from prenatal and young postnatal animals. In this study we examined the distribution of InsP 3 R isotypes 1-3 and RyR isotypes 1-3 in rat hippocampus during postnatal maturation, with a focus on InsP 3 R1 because it is most prominent in the hippocampus. InsP 3 R1 was observed in pyramidal cells and granule cells, InsP 3 R2 immunoreactivity was observed in perivascular astrocytes and endothelial cells, and InsP 3 R3 immunoreactivity was detected in axon terminals located in stratum pyramidale of CA1 and microvessels in stratum radiatum. RyR1 immunolabeling was enriched in CA1, RyR2 was most intense in CA3 and the dentate gyrus, and RyR3 immunolabeling was detected in all subfields of the hippocampus, but was most intense in stratum lacunosum-moleculare. During maturation from 2 to 10 weeks of age there was a shift in InsP 3 R1 immunoreactivity from a high density in the proximal apical dendrites to a uniform distribution along the dendrites. Independent of age, InsP 3 R1 immunoreactivity was observed to form clusters within the primary apical dendrite and at dendritic bifurcations of pyramidal neurons. As CA1 pyramidal neurons matured, InsP 3 R1 was often co-localized with the Ca 2+ binding protein calbindin D-28k. In contrast, InsP 3 R1 immunolabel was never co-localized with calbindin D-28k immunopositive interneurons located outside of stratum pyramidale or with parvalbumin, typically found in hippocampal basket cells, suggesting that InsP 3 R1s do not play a role in internal Ca 2+ release in these interneurons. These findings should help to interpret past functional studies and inform future studies examining the characteristics and consequences of InsP 3 R-mediated internal Ca 2+ release and Ca 2+ waves in hippocampal neurons.
Inositol 1,3,4,5-tetrakisphosphate as a second messenger—a special role in neurones?
Chemistry and Physics of Lipids, 1999
There has been much controversy over the possibility that inositol 1,3,4,5-tetrakisphosphate (InsP4) may have a second messenger function. A possible resolution to this controversy may stem from the recent cloning of two putative receptors for InsP4, GAP1IP4BP and GAP1m. Both these proteins are expressed at high levels in neurones, as is inositol 1,4,5-trisphosphate 3-kinase, the enzyme that makes InsP4. In this review we discuss the possible relevance of these high expression levels to the complex way in which neurones control Ca2+ and use it as a second messenger.
Journal of Biological Chemistry, 1997
D-myo-Inositol 1,4,5-trisphosphate (InsP 3) 5-phosphatase and 3-kinase are thought to be critical regulatory enzymes in the control of InsP 3 and Ca 2؉ signaling. In brain and many other cells, type I InsP 3 5-phosphatase is the major phosphatase that dephosphorylates InsP 3 and D-myo-inositol 1,3,4,5-tetrakisphosphate. The type I 5-phosphatase appears to be associated with the particulate fraction of cell homogenates. Molecular cloning of the human brain enzyme identifies a C-terminal farnesylation site CVVQ. Post-translational modification of this enzyme promotes membrane interactions and changes in specific activity. We have now compared the cytosolic Ca 2؉ ([Ca 2؉ ] i) responses induced by ATP, thapsigargin, and ionomycin in Chinese hamster ovary (CHO-K1) cells transfected with the intact InsP 3 5-phosphatase and with a mutant in which the C-terminal cysteine cannot be farnesylated. [Ca 2؉ ] i was also measured in cells transfected with an InsP 3 3-kinase construct encoding the A isoform. The Ca 2؉ oscillations detected in the presence of 1 M ATP in control cells were totally lost in 87.5% of intact (farnesylated) InsP 3 5-phosphatase-transfected cells, while such a loss occurred in only 1.1% of the mutant InsP 3 5-phosphatase-transfected cells. All cells overexpressing the InsP 3 3-kinase also responded with an oscillatory pattern. However, in contrast to control cells, the [Ca 2؉ ] i returned to base-line levels in between a couple of oscillations. The [Ca 2؉ ] i responses to thapsigargin and ionomycin were identical for all cells. The four cell clones compared in this study also behaved similarly with respect to capacitative Ca 2؉ entry. In permeabilized cells, no differences in extent of InsP 3-induced Ca 2؉ release nor in the threshold for InsP 3 action were observed among the four clones and no differences in the expression levels of the various InsP 3 receptor isoforms could be shown between the clones. Our data support the contention that the ATPinduced increase in InsP 3 concentration in transfected CHO-K1 cells is essentially restricted to the site of its
Brain Research, 1991
A quantitative autoradiographic study was made on the binding of the phosphatidylinositol system ligand [3H]inositol(1,4,5)-trisphosphate (IP3) to forebrain sections from rats decapitated various times after 10 min of forebrain ischemia. To investigate the effect of a deafferentation of the hippocampal CA1, kainic acid-induced CA3-1esioned rats with or without 10 min of cerebral ischemia, were also included. The highest binding was found in the hippocampal CA1. Ten min of cerebral ischemia did not change the binding significantly. Between 5 rain and 1 h of recirculation there was a 25-35% binding decline in all regions. In the CA1, where the pyramidal cells became necrotic 6 days after ischemia, there was a further decline to 16% of control. In the cortex, where there is no necrosis in this model, binding did not return to control values until day 14. Four days after a selective CA3 lesion with kainic acid, there was a significant 25% decline in the cortex, dentate gyrus and CA1, whereas in the necrotic CA3 binding declined to 54% of control. Ten min of ischemia did not alter this binding significantly. This decrease in calcium mobilizing intracellular receptors after ischemia and seizures could be due to increased membrane degradation, or to a more specific down-regulation following increased intracellular concentration of calcium and IP3.
Regulation of voltage-gated sodium channels is crucial to firing patterns that constitute the output of medium spiny neurons (MSN), projecting neurons of the striatum. This modulation is thus critical for the final integration of information processed within the striatum. It has been shown that the adenylate cyclase pathway reduces sodium currents in MSN through channel phosphorylation by cAMP-dependent protein kinase. However, it is unknown whether a phospholipase C (PLC)-mediated signaling cascade could also modulate voltage-gated sodium channels within MSN. Using the whole-cell patch clamp technique, we investigated the effects of activation of two key components in PLC-mediated signaling cascades: protein kinase C (PKC) and inositol-1,4,5-triphosphate (IP3) receptors on voltage-dependent sodium current. Cellular dialysis with phorbol 12-myristate 13-acetate, an activator of PKC, significantly reduced peak sodium current amplitude, while adenophostin A, an activator of IP3 receptors, significantly increased peak sodium current amplitude. This effect of adenophostin was abolished by calcium chelation or by FK506, an inhibitor of calcineurin. These results suggest an antagonistic role of PKC and IP3 in the modulation of striatal voltage-gated sodium channels, peak current amplitude being decreased through phosphorylation by PKC and increased through dephosphorylation by calcineurin.
Learning & memory (Cold Spring Harbor, N.Y.), 2016
We investigated the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) activated by preconditioning low-frequency afferent stimulation (LFS) in the subsequent induction of long-term potentiation (LTP) in CA1 neurons in hippocampal slices from mature guinea pigs. Induction of LTP in the field excitatory postsynaptic potential or the population spike by the delivery of high-frequency stimulation (HFS, a tetanus of 100 pulses at 100 Hz) to the Schaffer collateral-commissural pathway to CA1 neuron synapses was suppressed when group I metabotropic glutamate receptors (mGluRs) were activated prior to the delivery of HFS. LTP induction was also suppressed when CA1 synapses were preconditioned 60 min before HFS by LFS of 1000 pulses at 1 Hz and this effect was inhibited when the test stimulation delivered at 0.05 Hz was either halted or applied in the presence of an antagonist ofN-methyl-d-aspartate receptors, group I mGluRs, or IP3Rs during a 20-min period from 20 to 40 min after the e...