Differential effect of PKA on the Ca2+ release kinetics of the type I and III InsP3 receptors

Dyer, Jeanette L.; Mobasheri, Hamid; Lea, E.J.A.; Dawson, Alan P.; Michelangeli, Francesco

doi:10.1016/s0006-291x(03)00120-7

Cited by 19 publications

(18 citation statements)

References 22 publications

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“…The inability of maximally activated PKA to substantially phosphorylate exogenous IP 3 R2 expressed in HEK cells (Fig 1) is consistent with findings that endogenous IP 3 R2 in AR42J cells is only very weakly phosphorylated by PKA [9], and that PKA catalytic subunit does not affect IP 3 -mediated Ca 2+ release in permeabilized cells that predominantly express IP 3 R2 [11]. Taken together, these data indicate that IP 3 R2 is not a physiological substrate for PKA.…”

Section: Discussionsupporting

confidence: 88%

“…Anti-pS934 exhibited minor immunoreactivity towards wild-type IP 3 R3 (IP 3 R3 SSS ; lane 3) and IP 3 R3 mutated at S 916 and S 1832 (IP 3 R3 ASA ; lane 9) in the absence of stimulus, and this was increased substantially under conditions of maximal IP 3 R phosphorylation (lanes 4 and 10). Anti-pS934 did not, however, exhibit any immunoreactivity towards IP 3 R3 mutated at S 934 (IP 3 R3 SAS ; lanes 7-8), IP 3 R3 mutated at S 916 , S 934 , and S 1832 (IP 3 R3 AAA ; lanes 5-6), or wild-type IP 3 R1 (IP 3 R1 SS ; lanes [11][12] in the absence or presence of forskolin, demonstrating that it is entirely specific towards IP 3 R3 phosphorylated at S 934 . This was confirmed by immunofluorescence microscopy of transfected COS cells.…”

Section: Validation Of Anti-ps934mentioning

confidence: 99%

“…Despite these similarities, however, expression of IP 3 R types varies between tissues [4,5] and subtle differences in their functional properties, such as their regulation by IP 3 , Ca 2+ and ATP, are apparent [3,[6][7][8]. Functional differences between the three receptor types may also arise from their differential phosphorylation by cAMP-dependent protein kinase (PKA) [9][10][11] but, with the exception of IP 3 R1, there is no clear consensus regarding the functional consequences of these phosphorylation events.…”

Section: Introductionmentioning

confidence: 99%

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Calcium mobilization via type III inositol 1,4,5-trisphosphate receptors is not altered by PKA-mediated phosphorylation of serines 916, 934, and 1832

Soulsby

Wojcikiewicz

2007

Cell Calcium

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Several studies have shown that PKA-mediated phosphorylation of IP 3 R1 at serines S 1588 and S 1755 enhances the receptor's ability to mobilize Ca 2+ . In contrast, much less is known about whether Ca 2+ mobilization via IP 3 R2 and IP 3 R3 is regulated by PKA. We report here that IP 3 R2 is only very weakly phosphorylated in response to PKA activation and is probably not a physiological substrate for this kinase. IP 3 R3, however, is known to be phosphorylated by PKA at three sites (S 916 , S 934 and S 1832 ) and, thus, we examined how phosphorylation of these sites affects Ca 2+ mobilization in DT40-3KO cells stably expressing either exogenous wild-type or mutant IP 3 R3s; an antibody raised against phospho-serine 934 of IP 3 R3 was used to demonstrate that the exogenous IP 3 R3s are strongly phosphorylated in response to PKA activation. Surprisingly, our data show that IP 3 R3-mediated Ca 2+ mobilization is unaffected by phosphorylation of S 916 , S 934 and S 1832 . In contrast, phosphorylation of exogenous IP 3 R1 (monitored with an antibody against phospho-serine 1755) enhances Ca 2+ mobilization, indicating that DT40-3KO cells have the capacity to respond to phosphorylation of IP 3 Rs. Overall, these data suggest that modification of Ca 2+ flux may not be the primary effect of IP 3 R3 phosphorylation by PKA.

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Section: Discussionsupporting

confidence: 88%

Section: Validation Of Anti-ps934mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Calcium mobilization via type III inositol 1,4,5-trisphosphate receptors is not altered by PKA-mediated phosphorylation of serines 916, 934, and 1832

Soulsby

Wojcikiewicz

2007

Cell Calcium

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“…PKA has been found to modulate calcium-release through the inositol 1,4,5-trisphosphate (IP 3 ) receptor. However, the effects of PKA on IP 3 receptors are complex and may vary with the receptor subtype (1,2). Recent studies have also demonstrated that the Epac pathway may modulate levels of intracellular calcium by regulating movement through the calcium-dependent calcium-release channel (3).…”

Section: Discussionmentioning

confidence: 99%

Effect of ligands that increase cAMP on caerulein-induced zymogen activation in pancreatic acini

Zhao

Kolodecik

Karne

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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The pathological activation of proteases within the pancreatic acinar cell is critical to initiating pancreatitis. Stimulation of acinar cells with supraphysiological concentrations of the CCK analog caerulein (CER) leads to protease activation and pancreatitis. Agents that sensitize the acinar cell to the effects of CCK might contribute to disease. The effects of physiological ligands that increase acinar cell cAMP [secretin, VIP, and pituitary adenylate cyclase activating peptide (PACAP)] on CER-induced responses were examined in isolated rat pancreatic acini. Each ligand sensitized the acinar cell to zymogen activation by physiological concentrations of CER (0.1 nM). VIP and PACAP but not secretin also enhanced activation by supraphysiological concentrations of CER (0.1 μM). A cell-permeable cAMP analog also sensitized the acinar cell to CER-induced activation. The cAMP antagonist Rp-8-Br-cAMP inhibited these sensitizing effects. These findings suggest that ligands that increase acinar cell cAMP levels can sensitize the acinar cell to the effects of CCK-induced zymogen activation. Keywordscaerulein; chymotrypsin; secretin; trypsin THE PREMATURE ACTIVATION of digestive zymogens within the pancreatic acinar cell contributes to the initiation of pancreatitis. In the rodent pancreas, ligands such as CCK or the muscarinic agonist carbachol can cause zymogen activation in isolated pancreatic acini. These ligands activate specific G protein-linked receptors that stimulate phospholipase C and increase cytosolic Ca 2+ . Several reports (7,9) have observed that zymogen activation within the acinar cell requires an increase in cytosolic Ca 2+ . CCK-induced activation depends on the presence of extracellular Ca 2+ and an increase in cytosolic Ca 2+ (9). Removal of extracellular Ca 2+ or chelation of intracellular Ca 2+ blocks caerulein (a CCK homolog)-induced trypsin activation (7,9). Whether an increase in intracellular Ca 2+ alone is sufficient to cause activation is controversial. Increasing cytosolic Ca 2+ by thapsigargin was found to cause zymogen activation in one study but not in another (7,9). Thus additional signaling pathways may act independently or with Ca 2+ to cause zymogen activation.The pancreatic acinar cell has receptors for pathways that are coupled to increasing both cytosolic Ca 2+ and cAMP. Stimulation of acinar cell CCK or muscarinic receptors is linked to increased cytosolic Ca 2+ . Secretin, pituitary adenylate cyclase activating peptide (PACAP), and VIP stimulate receptors that are primarily coupled to cAMP generation. However, some 2+ and cAMP (5). Moreover, although physiological concentrations of CCK do not cause a measurable increase in cAMP, they do activate cAMP-dependent protein kinase (5). Similarly, secretin has been reported in some but not all studies to not only increase cellular cAMP, but to also stimulate phospholipase C activity causing an increase in cytosolic Ca 2+ in the acinar cell (10,12). Because ligands that increase both acinar cell Ca 2+ and cAMP are released in...

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“…Effects of PKA-mediated phosphorylation of wildtype InsP 3 R-1 have been studied at the single-channel level (110,123,456). Phosphorylation by PKA of reconstituted recombinant rat InsP 3 R-1 enhanced single channel P o approximately fivefold from ϳ0.07 to ϳ0.35 without affecting the narrow bell-shaped [Ca 2ϩ ] dependence (456).…”

Section: Phosphorylation By Pkamentioning

confidence: 99%

Inositol Trisphosphate Receptor Ca²⁺Release Channels

Foskett

White²,

Cheung³

et al. 2007

Physiological Reviews

1,067

1,334

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The inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3Rs) are a family of Ca2+ release channels localized predominately in the endoplasmic reticulum of all cell types. They function to release Ca2+ into the cytoplasm in response to InsP3 produced by diverse stimuli, generating complex local and global Ca2+ signals that regulate numerous cell physiological processes ranging from gene transcription to secretion to learning and memory. The InsP3R is a calcium-selective cation channel whose gating is regulated not only by InsP3, but by other ligands as well, in particular cytoplasmic Ca2+. Over the last decade, detailed quantitative studies of InsP3R channel function and its regulation by ligands and interacting proteins have provided new insights into a remarkable richness of channel regulation and of the structural aspects that underlie signal transduction and permeation. Here, we focus on these developments and review and synthesize the literature regarding the structure and single-channel properties of the InsP3R.

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Differential effect of PKA on the Ca2+ release kinetics of the type I and III InsP3 receptors

Cited by 19 publications

References 22 publications

Calcium mobilization via type III inositol 1,4,5-trisphosphate receptors is not altered by PKA-mediated phosphorylation of serines 916, 934, and 1832

Calcium mobilization via type III inositol 1,4,5-trisphosphate receptors is not altered by PKA-mediated phosphorylation of serines 916, 934, and 1832

Effect of ligands that increase cAMP on caerulein-induced zymogen activation in pancreatic acini

Inositol Trisphosphate Receptor Ca²⁺Release Channels

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Differential effect of PKA on the Ca2+ release kinetics of the type I and III InsP3 receptors

Cited by 19 publications

References 22 publications

Calcium mobilization via type III inositol 1,4,5-trisphosphate receptors is not altered by PKA-mediated phosphorylation of serines 916, 934, and 1832

Calcium mobilization via type III inositol 1,4,5-trisphosphate receptors is not altered by PKA-mediated phosphorylation of serines 916, 934, and 1832

Effect of ligands that increase cAMP on caerulein-induced zymogen activation in pancreatic acini

Inositol Trisphosphate Receptor Ca2+Release Channels

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Inositol Trisphosphate Receptor Ca²⁺Release Channels