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, Matthew; Wojcikiewicz, Richard J.H.

doi:10.1016/j.ceca.2006.12.002

Cited by 30 publications

(30 citation statements)

References 32 publications

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“…Previous studies have shown that exogenous IP 3 Rs are expressed at high levels in HEK 293T cells, such that the contribution of endogenous IP 3 Rs to biochemical measurements (e.g. IP 3 R phosphorylation) is negligible or undetectable (31). Immunoprecipitation of IP 3 R1 and IP 3 R2 recovered a considerable amount of 3F-Bok (Fig.…”

Section: Bok Associates With Ipmentioning

confidence: 99%

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The Bcl-2 Protein Family Member Bok Binds to the Coupling Domain of Inositol 1,4,5-Trisphosphate Receptors and Protects Them from Proteolytic Cleavage

Schulman

Wright

Kaufmann

et al. 2013

Journal of Biological Chemistry

114

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Section: Bok Associates With Ipmentioning

confidence: 99%

“…4C). Vectors encoding IP 3 R1-3 have been described (31). The authenticity of all cDNAs was confirmed by DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

The Bcl-2 Protein Family Member Bok Binds to the Coupling Domain of Inositol 1,4,5-Trisphosphate Receptors and Protects Them from Proteolytic Cleavage

Schulman

Wright

Kaufmann

et al. 2013

Journal of Biological Chemistry

114

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“…Establishing the PKA phosphorylation site(s) and subsequently performing mutagenesis of the putative sites in InsP 3 R2 are required to definitively rule out these and other possible mechanisms for the increased Ca 2ϩ signal. Although PKA has been shown to phosphorylate InsP 3 R2 in a number of studies by independent groups (21,26,28), the site(s) of phosphorylation are not known. Experiments were performed following transient overexpression of InsP 3 R2 in COS-7 cells.…”

Section: Activation Of Pka Enhances Camentioning

confidence: 99%

Protein Kinase A Increases Type-2 Inositol 1,4,5-Trisphosphate Receptor Activity by Phosphorylation of Serine 937

Betzenhauser

Fike

Wagner

et al. 2009

Journal of Biological Chemistry

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Hormones, neurotransmitters, and growth factors stimulate the production of InsP 3 3 and Ca 2ϩ signals in virtually all cell types (1). The ubiquitous nature of this mode of signaling dictates that this pathway does not exist in isolation; indeed, a multitude of additional signaling pathways can be activated simultaneously. A prime example of this type of "cross-talk" between independently activated signaling systems results from the parallel activation of cAMP and Ca 2ϩ signaling pathways (2, 3). Interactions between these two systems occur in numerous distinct cell types with various physiological consequences (3-6). Given the central role of InsP 3 R in Ca 2ϩ signaling, a major route of modulating the spatial and temporal features of Ca 2ϩ signals following cAMP production is potentially through PKA phosphorylation of the InsP 3 R isoform(s) expressed in a particular cell type. There are three InsP 3 R isoforms (InsP 3 R1, InsP 3 R2, and InsP 3 R3) expressed to varying degrees in mammalian cells (7,8). InsP 3 R1 is the major isoform expressed in the nervous system, but it is less abundant compared with other subtypes in non-neuronal tissues (8). Ca 2ϩ release via InsP 3 R2 and InsP 3 R3 predominate in these tissues. InsP 3 R2 is the major InsP 3 R isoform in many cell types, including hepatocytes (7, 8), astrocytes (9, 10), cardiac myocytes (11), and exocrine acinar cells (8,12). Activation of PKA has been demonstrated to enhance InsP 3 -induced Ca 2ϩ signaling in hepatocytes (13) and parotid acinar cells (4,14). Although PKA phosphorylation of InsP 3 R2 is a likely causal mechanism underlying these effects, the functional effects of phosphorylation have not been determined in cells unambiguously expressing InsP 3 R2 in isolation. Furthermore, the molecular determinants of PKA phosphorylation of this isoform are not known.PKA-mediated phosphorylation is an efficient means of transiently and reversibly regulating the activity of the InsP 3 R. InsP 3 R1 was identified as a major substrate of PKA in the brain prior to its identification as the InsP 3 R (15, 16). However, until recently, the functional consequences of phosphorylation were unresolved. Initial conflicting results were reported indicating that phosphoregulation of InsP 3 R1 could result in either inhibition or stimulation of receptor activity (16,17). Mutagenic strategies were employed by our laboratory to clarify this discrepancy. These studies unequivocally assigned phosphorylation-dependent enhanced Ca 2ϩ release and InsP 3 R1 activity at the single channel level, through phosphorylation at canonical PKA consensus motifs at Ser 1589 and Ser 1755 . The sites responsible were also shown to be specific to the particular InsP 3 R1 splice variant (18). These data were also corroborated by replacing the relevant serines with glutamates in a strategy designed to construct "phosphomimetic" InsP 3 R1 by mimicking the negative charge added by phosphorylation (19,20). Of particular note, however, although all three isoforms are substrates for PKA, neither o...

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“…Pharmacological studies have shown that the calcium waves themselves involve an inositol-trisphosphate receptor (IP 3 R) pathway (Filosa et al, 2004), although the exact subtype of IP 3 Rs has not yet been determined (Yamamoto-Hino et al, 1995;Sharp et al, 1999;Holtzclaw et al, 2002, Cotrina andNedergaard, 2005). Although the three IP 3 R subtypes have similar channel properties, calcium release from the various subtypes can be differentially modulated by calcium, ATP, and phosphorylation (Foskett et al, 2007;Soulsby and Wojcikiewicz, 2007), thus modulating the resultant calcium wave.…”

mentioning

confidence: 97%

Limited intravascular coupling in the rodent brainstem and retina supports a role for glia in regional blood flow

Kuo

Chan‐Ling

Wojcikiewicz

et al. 2008

J of Comparative Neurology

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Regional synaptic activity induces local increases in perfusion that are coupled to upstream vasodilation and improved blood flow. In the cerebral circulation, it has been proposed that astrocytes mediate the link between the initiating stimulus and local vasodilation through propagated intracellular calcium waves. In the systemic circulation the mechanism by which local vasodilation triggers upstream alterations in blood flow involves electrotonic propagation of hyperpolarization via endothelial gap junctions, although less is known concerning the cerebral circulation. The present study aimed to investigate the extent of coupling in microvessels of the rodent brainstem and retina and the subtypes of intracellular calcium stores that might mediate astrocytic signaling. Within the brainstem, connexins (Cxs) 37 and 40 were restricted to the endothelium of pial vessels and larger penetrating arterioles, whereas astrocytic Cxs30 and 43 were found closely associated with pre- and postsynaptic neurons and nearby microvessels. Within the rat retina, Cxs37 and 40 were expressed in large radiating arterioles, but were not found in smaller vessels on the retinal surface or in the deeper retinal layers. These Cxs were absent from all retinal vessels in mice. Astrocytes, expressing Cxs30 and 43 in the rat, but only Cx43 in the mouse, were found closely associated with superficial, but not deeper blood vessels. Inositol-trisphosphate receptors (IP(3)R) 1 and 2 were expressed within brainstem astrocytes, whereas IP(3)R1 and 3 were expressed within retinal astrocytes. Limited intravascular coupling and the proximity of astrocytic networks to blood vessels supports a role for glia in activity-dependent alterations in central blood flow.

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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

Cited by 30 publications

References 32 publications

The Bcl-2 Protein Family Member Bok Binds to the Coupling Domain of Inositol 1,4,5-Trisphosphate Receptors and Protects Them from Proteolytic Cleavage

The Bcl-2 Protein Family Member Bok Binds to the Coupling Domain of Inositol 1,4,5-Trisphosphate Receptors and Protects Them from Proteolytic Cleavage

Protein Kinase A Increases Type-2 Inositol 1,4,5-Trisphosphate Receptor Activity by Phosphorylation of Serine 937

Limited intravascular coupling in the rodent brainstem and retina supports a role for glia in regional blood flow

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