Modulation of Type 1 Inositol (1,4,5)-Trisphosphate Receptor Function by Protein Kinase A and Protein Phosphatase 1α

Tang, Tie Shan; Tu, Huiping; Wang, Zhengnan; Bezprozvanny, Ilya

doi:10.1523/jneurosci.23-02-00403.2003

Cited by 146 publications

(188 citation statements)

References 67 publications

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“…tuted into lipid bilayers has reported a similar increase in InsP 3 R sensitivity to InsP 3 but that the bell-shaped Ca 2ϩ sensitivity of channel opening is not altered following phosphorylation of the InsP 3 R-1 (20). These findings suggest that modulation of the Ca 2ϩ sensitivity of channel activity is unlikely to account for the increased apparent sensitivity of the receptor, at least in this form of the InsP 3 R-1.…”

Section: Sensitivity Of S2ϩ Insp 3 R-1 and Phosphorylation Site Mutants-mentioning

confidence: 85%

Functional Consequences of Phosphomimetic Mutations at Key cAMP-dependent Protein Kinase Phosphorylation Sites in the Type 1 Inositol 1,4,5-Trisphosphate Receptor

Wagner

Joseph

et al. 2004

Journal of Biological Chemistry

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Regulation of Ca 2؉ release through inositol 1,4,5-trisphosphate receptors (InsP 3 R) has important consequences for defining the particular spatio-temporal properties of intracellular Ca 2؉ signals. In this study, regulation of Ca 2؉ release by phosphorylation of type 1 InsP 3 R (InsP 3 R-1) was investigated by constructing "phosphomimetic" charge mutations in the functionally important phosphorylation sites of both the S2؉ and S2؊ InsP 3 R-1 splice variants. Ca 2؉ release was investigated following expression in Dt-40 3ko cells devoid of endogenous InsP 3 R. In cells expressing either the S1755E S2؉ or S1589E/S1755E S2؊ InsP 3 R-1, InsP 3 -induced Ca 2؉ release was markedly enhanced compared with nonphosphorylatable S2؉ S1755A and S2؊ S1589A/ S1755A mutants. Ca 2؉ release through the S2؊ S1589E/ S1755E InsP 3 R-1 was enhanced ϳ8-fold over wild type and ϳ50-fold when compared with the nonphosphorylatable S2؊ S1589A/S1755A mutant. In cells expressing S2؊ InsP 3 R-1 with single mutations in either S1589E or S1755E, the sensitivity of Ca 2؉ release was enhanced ϳ3-fold; sensitivity was midway between the wild type and the double glutamate mutation. Paradoxically, forskolin treatment of cells expressing either single Ser/ Glu mutation failed to further enhance Ca 2؉ release. The sensitivity of Ca 2؉ release in cells expressing S2؉ S1755E InsP 3 R-1 was comparable with the sensitivity of S2؊ S1589E/S1755E InsP 3 R-1. In contrast, mutation of S2؉ S1589E InsP 3 R-1 resulted in a receptor with comparable sensitivity to wild type cells. Expression of S2؊ S1589E/S1755E InsP 3 R-1 resulted in robust Ca 2؉ oscillations when cells were stimulated with concentrations of ␣-IgM antibody that were threshold for stimulation in S2؊ wild type InsP 3 R-1-expressing cells. However, at higher concentrations of ␣-IgM antibody, Ca 2؉ oscillations of a similar period and magnitude were initiated in cells expressing either wild type or S2؊ phosphomimetic mutations. Thus, regulation by phosphorylation of the functional sensitivity of InsP 3 R-1 appears to define the threshold at which oscillations are initiated but not the frequency or amplitude of the signal when established.Inositol 1,4,5-trisphosphate receptors are intracellular ion channels that function to couple the activation of cell surface receptors for neurotransmitters, hormones, and growth factors to the initiation of intracellular Ca 2ϩ release (1). Three genes have been cloned that encode distinct proteins of a molecular mass of ϳ300 kDa, named the type 1 (InsP 3 R-1), 1 type 2 (InsP 3 R-2), and type 3 (InsP 3 R-3) InsP 3 Rs (2-4). In addition, multiple receptor proteins with distinct tissue distributions are produced by alternate splicing of the type 1 receptor gene (5, 6). Most cells express multiple isoforms of InsP 3 R (7). Furthermore, the expression level and complement of receptors differ in individual tissues, and this together with regulation of the activity of the channel is thought to be a major determinant of the rich diversity of Ca 2ϩ signaling events observed ...

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Section: Sensitivity Of S2ϩ Insp 3 R-1 and Phosphorylation Site Mutants-mentioning

confidence: 85%

Functional Consequences of Phosphomimetic Mutations at Key cAMP-dependent Protein Kinase Phosphorylation Sites in the Type 1 Inositol 1,4,5-Trisphosphate Receptor

Wagner

Joseph

et al. 2004

Journal of Biological Chemistry

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“…PKA phosphorylates InsP 3 R1 at two sites, Ser-1589 and Ser-1755 (31)(32)(33)(34)(35)(36). PKA phosphorylation activates InsP 3 R1 by increasing the sensitivity of InsP 3 R1 to activation by InsP 3 (35,(37)(38)(39). In previous biochemical studies, we discovered direct association of neuro-nal InsP 3 R1 with PP1␣ (39) and showed that the InsP 3 R1⅐AKAP9⅐PKA complex is formed in the brain (40).…”

Section: From the Department Of Physiology University Of Texas Southmentioning

confidence: 99%

“…PKA phosphorylates InsP 3 R1 at two sites, Ser-1589 and Ser-1755 (31-36). PKA phosphorylation activates InsP 3 R1 by increasing the sensitivity of InsP 3 R1 to activation by InsP 3 (35,(37)(38)(39). In previous biochemical studies, we discovered direct association of neuro-* This work was supported by the Robert A. Welch Foundation, the Hereditary Disease Foundation, and National Institutes of Health Grant R01 NS38082 (to I.…”

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confidence: 99%

Dopamine Receptor-mediated Ca2+ Signaling in Striatal Medium Spiny Neurons

Tang

Bezprozvanny

2004

Journal of Biological Chemistry

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Inositol 1,4,5-trisphosphate (InsP 3 ) and cAMP are the two second messengers that play an important role in neuronal signaling. Here, we investigated the interactions of InsP 3 -and cAMP-mediated signaling pathways activated by dopamine in striatal medium spiny neurons (MSN). We found that in ϳ40% of the MSN, application of dopamine elicited robust repetitive Ca 2؉ transients (oscillations). In pharmacological experiments with specific agonists and antagonists, we found that the observed Ca 2؉ oscillations were triggered by activation of D1 class dopamine receptors (DARs). We further demonstrated that activation of phospholipase C was required for induction of dopamine- Dopamine is an important transmitter and neuromodulator in the brain. The cellular mechanisms by which dopamine affects neuronal function are only beginning to be elucidated (1, 2). Striatal medium spiny neurons (MSN) 1 express multiple subtypes of dopamine receptors (DARs) (3-5). On the basis of their molecular structure and pharmacological properties, DARs are divided into the D1 class (D1R and D5R) and D2 class (D2R, D3R, and D4R) (6). D1 class DARs are coupled to G s/olf , activation of adenylyl cyclase, and cAMP production (3). Activation of D2 class DARs has dual effects of inhibiting cAMP production (3) and activating phospholipase C␤ (PLC␤) (7). A putative D1 class DAR subtype coupled to PLC activation and phosphatidylinositol 4,5-diphosphate hydrolysis, but not to cAMP production, has been postulated (8 -10), but has not yet been isolated or cloned. Recently, a specific agonist for this receptor (SKF83959) was identified (11). The D1R-binding protein calcyon has been isolated by yeast two-hybrid methods (12). Association of D1/D5 receptors with calcyon enables coupling of D1/D5 receptors with G q/11 , resulting in PLC activation and inositol 1,4,5-trisphosphate (InsP 3 ) generation (12, 13). Cross-talk between cAMP and Ca 2ϩ signaling pathways plays an important role in dopaminergic signaling in the neostriatum (1). Activation of D1 class DARs enhances L-type Ca 2ϩ channel activity (14 -16) and currents via the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (17) and the N-methyl-D-aspartic acid (NMDA) receptor (18,19). In contrast, activation of D2 class DARs reduces L-type Ca 2ϩ currents (7) and NMDA receptor activity (20). D1/D5 receptormediated facilitation of L-type Ca 2ϩ channels and AMPA and NMDA receptors results from increased phosphorylation of these channels by protein kinase A (PKA) (16, 21) and decreased dephosphorylation of these channels by protein phosphatase-1 (PP1) (17,22,23). DARPP-32 (dopamine-and cAMPregulated phosphoprotein of M r 32,000) (24, 25) is partly responsible for inhibition of PP1 activity following activation of D1/D5 receptors (26). DARPP-32 phosphorylated by PKA at a single threonine residue (Thr-34) is transformed into a potent inhibitor of PP1, which in turn regulates the phosphorylation state of many neurotransmitter receptors and voltage-gated ion channels (1).The type 1 inos...

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“…The interaction of specific accessory proteins has been demonstrated to either positively or negatively regulate IP 3 R opening, with consequent alteration of cellular Ca 2+ signals (e.g. [25,26]). Although most of the data exploring IP 3 R-binding proteins has been derived from studies of neuronal IP 3 Rs, it is likely that cardiac IP 3 Rs form similar macromolecular complexes.…”

Section: The Abc Of Ip 3 : Where Does It Come From and Where Does It Go?mentioning

confidence: 99%

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

173

149

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Inositol 1,4,5-trisphosphate (IP 3 ) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP 3 from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The major action of IP 3 , which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca 2+ release from endogenous stores through IP 3 receptors (IP 3 Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca 2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP 3 Rs (∼100:1), and furthermore they experience substantial fluxes of Ca 2+ with each heartbeat. Therefore, the role of IP 3 and IP 3 -mediated Ca 2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP 3 Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP 3 Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca 2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP 3 Rs and membrane receptors that couple to PLC/IP 3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP 3 signaling in the pathology of these diseases. Thus, IP 3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation-contraction and excitation-transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure. KeywordsInositol 1,4,5-trisphosphate; Cardiac myocyte; Calcium; Inotropy; Arrhythmias; Nucleus; Hypertrophy © 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: jens.kockskaemper@meduni-graz.at (J. Kockskämper).. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The discovery of IP 3A quarter of a century ago it was shown that D-myo inositol 1,4,5-trisphosphate (IP 3 ) releases Ca 2+ from a non-mitochondrial internal Ca 2+ store [1]. Since this hallmark discovery, IP 3 has emerged as a ubiquitous intracellular messenger, releasing Ca 2+ from stores through activation of IP 3 receptors (IP 3 Rs) in almost all eukaryotic cells. The major IP 3 -sensitive intracellular Ca 2+ store is the endoplasmic reticulum. However, IP 3 has also been shown to release Ca 2+ stored in other compartments, such as the Golgi and the nuclear envelope [2]. In addition, IP 3 Rs are present on the plasma membrane of some cell types, where they can gate Ca 2+ influx [3]. A crucial role for IP 3 -dependent Ca 2+ release has been demonstrated in many mammalian cell types, ranging from tiny platelets, where it initiates blood clottin...

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Modulation of Type 1 Inositol (1,4,5)-Trisphosphate Receptor Function by Protein Kinase A and Protein Phosphatase 1α

Cited by 146 publications

References 67 publications

Functional Consequences of Phosphomimetic Mutations at Key cAMP-dependent Protein Kinase Phosphorylation Sites in the Type 1 Inositol 1,4,5-Trisphosphate Receptor

Functional Consequences of Phosphomimetic Mutations at Key cAMP-dependent Protein Kinase Phosphorylation Sites in the Type 1 Inositol 1,4,5-Trisphosphate Receptor

Dopamine Receptor-mediated Ca2+ Signaling in Striatal Medium Spiny Neurons

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

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