Phosphorylation of Ser
 1928
 mediates the enhanced activity of the L-type Ca
 2+
 channel Ca
 v
 1.2 by the β
 2
 -adrenergic receptor in neurons

Qian, Hai; Patriarchi, Tommaso; Price, Jennifer L.; Matt, Lucas; Lee, Boram; Nieves‐Cintrón, Madeline; Buonarati, Olivia R.; Chowdhury, Dhrubajyoti; Nanou, Evanthia; Nystoriak, Matthew A.; Catterall, William A.; Poomvanicha, Montatip; Hofmann, Franz; Navedo, Manuel F.; Hell, Johannes

doi:10.1126/scisignal.aaf9659

Cited by 100 publications

(125 citation statements)

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“…(64). However, this phosphorylation event does not seem to be important for PKA-dependent regulation of Ca V 1.2 channel activity in cardiac cells (21).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, Qian et al . report that S1928A mice have impaired long-term potentiation and compromised β-adrenergic–mediated stimulation of Ca V 1.2 activity by PKA in neurons, demonstrating a key role for Ser 1928 in β-adrenergic regulation of Ca V 1.2 channel activity and neuronal function (64). The molecular mechanisms underlying these marked tissue-specific differences are unclear but may involve functional heterogeneity among distinct tissue-specific channel splice variants, a unique phosphorylation profile of α1 C , posttranslational regulation of other interacting proteins at distinct sites, or differential interaction with or regulation by different scaffold proteins and accessory subunits.…”

Section: Discussionmentioning

confidence: 99%

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Ser ¹⁹²⁸ phosphorylation by PKA stimulates the L-type Ca ²⁺ channel Ca _V 1.2 and vasoconstriction during acute hyperglycemia and diabetes

et al. 2017

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Hypercontractility of arterial myocytes and enhanced vascular tone during diabetes are, in part, attributed to the effects of increased glucose (hyperglycemia) on L-type CaV1.2 channels. In murine arterial myocytes, kinase-dependent mechanisms mediate the increase in CaV1.2 activity in response to increased extracellular glucose. We identified a subpopulation of the CaV1.2 channel pore-forming subunit (α1C) within nanometer proximity of protein kinase A (PKA) at the sarcolemma of murine and human arterial myocytes. This arrangement depended upon scaffolding of PKA by an A-kinase anchoring protein 150 (AKAP150) in mice. Glucose-mediated increases in CaV1.2 channel activity were associated with PKA activity, leading to α1C phosphorylation at Ser1928. Compared to arteries from low-fat diet (LFD)–fed mice and nondiabetic patients, arteries from high-fat diet (HFD)–fed mice and from diabetic patients had increased Ser1928 phosphorylation and CaV1.2 activity. Arterial myocytes and arteries from mice lacking AKAP150 or expressing mutant AKAP150 unable to bind PKA did not exhibit increased Ser1928 phosphorylation and CaV1.2 current density in response to increased glucose or to HFD. Consistent with a functional role for Ser1928 phosphorylation, arterial myocytes and arteries from knockin mice expressing a CaV1.2 with Ser1928 mutated to alanine (S1928A) lacked glucose-mediated increases in CaV1.2 activity and vasoconstriction. Furthermore, the HFD-induced increases in CaV1.2 current density and myogenic tone were prevented in S1928A knockin mice. These findings reveal an essential role for α1C phosphorylation at Ser1928 in stimulating CaV1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes.

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“…(64). However, this phosphorylation event does not seem to be important for PKA-dependent regulation of Ca V 1.2 channel activity in cardiac cells (21).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ser ¹⁹²⁸ phosphorylation by PKA stimulates the L-type Ca ²⁺ channel Ca _V 1.2 and vasoconstriction during acute hyperglycemia and diabetes

et al. 2017

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“…I’m Annalisa VanHook, and today I’ll be talking with Johannes Hell and Manuel Navedo about tissue-specific regulation of L-type calcium channels (1, 2). …”

Section: Transcriptmentioning

confidence: 99%

“…In the first paper from your groups, you looked at how the activity of L-type calcium channels is controlled differently in neurons and cardiac cells (1). First of all, how do L-type calcium channels contribute to neuronal and cardiac cell functions?…”

Section: Transcriptmentioning

confidence: 99%

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Science Signaling Podcast for 24 January 2017: Tissue-specific regulation of L-type calcium channels

2017

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This Podcast features an interview with Johannes Hell and Manuel Navedo, senior authors of two Research Articles that appear in the 24 January 2017 issue of Science Signaling, about tissue-specific regulation of the L-type calcium channel CaV1.2. This channel is present in many tissues, including the heart, vasculature, and brain, and allows calcium to flow into cells when it is activated. Signaling through the β-adrenergic receptor (βAR) stimulates CaV1.2 activity in heart cells and neurons to accelerate heart rate and increase neuronal excitability, respectively. Using mouse models, Qian et al. found that βAR-mediated enhancement of CaV1.2 activity in the brain required phosphorylation of Ser1928, whereas βAR-mediated enhancement of CaV1.2 activity in the heart did not require phosphorylation of this residue. In a related study, Nystoriak et al. demonstrated that phosphorylation of Ser1928 in arterial myocytes was required for vasoconstriction during acute hyperglycemia and in diabetic mice. These findings demonstrate tissue-specific differences in CaV1.2 regulation and suggest that it may be possible to design therapies to target this channel in specific tissues.

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Compartmentalized signaling in the soma: Coordination of electrical and protein kinase A signaling at neuronal ER‐plasma membrane junctions

Vierra

2024

BioEssays

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Neuronal information processing depends on converting membrane depolarizations into compartmentalized biochemical signals that can modify neuronal activity and structure. However, our understanding of how neurons translate electrical signals into specific biochemical responses remains limited, especially in the soma where gene expression and ion channel function are crucial for neuronal activity. Here, I emphasize the importance of physically compartmentalizing action potential‐triggered biochemical reactions within the soma. Emerging evidence suggests that somatic endoplasmic reticulum–plasma membrane (ER‐PM) junctions are specialized organelles that coordinate electrical and biochemical signaling. The juxtaposition of ion channels and signaling proteins at a prominent subset of these sites enables compartmentalized calcium and cAMP‐dependent protein kinase (PKA) signaling. I explore the hypothesis that these PKA‐containing ER‐PM junctions serve as critical sites for translating membrane depolarizations into PKA signals and identify key gaps in knowledge of the assembly, regulation, and neurobiological functions of this somatic signaling system.

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Phosphorylation of Ser ¹⁹²⁸ mediates the enhanced activity of the L-type Ca ²⁺ channel Ca _v 1.2 by the β ₂ -adrenergic receptor in neurons

Cited by 100 publications

References 104 publications

Ser ¹⁹²⁸ phosphorylation by PKA stimulates the L-type Ca ²⁺ channel Ca _V 1.2 and vasoconstriction during acute hyperglycemia and diabetes

Ser ¹⁹²⁸ phosphorylation by PKA stimulates the L-type Ca ²⁺ channel Ca _V 1.2 and vasoconstriction during acute hyperglycemia and diabetes

Science Signaling Podcast for 24 January 2017: Tissue-specific regulation of L-type calcium channels

Compartmentalized signaling in the soma: Coordination of electrical and protein kinase A signaling at neuronal ER‐plasma membrane junctions

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Phosphorylation of Ser 1928 mediates the enhanced activity of the L-type Ca 2+ channel Ca v 1.2 by the β 2 -adrenergic receptor in neurons

Cited by 100 publications

References 104 publications

Ser 1928 phosphorylation by PKA stimulates the L-type Ca 2+ channel Ca V 1.2 and vasoconstriction during acute hyperglycemia and diabetes

Ser 1928 phosphorylation by PKA stimulates the L-type Ca 2+ channel Ca V 1.2 and vasoconstriction during acute hyperglycemia and diabetes

Science Signaling Podcast for 24 January 2017: Tissue-specific regulation of L-type calcium channels

Compartmentalized signaling in the soma: Coordination of electrical and protein kinase A signaling at neuronal ER‐plasma membrane junctions

Contact Info

Product

Resources

About

Phosphorylation of Ser ¹⁹²⁸ mediates the enhanced activity of the L-type Ca ²⁺ channel Ca _v 1.2 by the β ₂ -adrenergic receptor in neurons

Ser ¹⁹²⁸ phosphorylation by PKA stimulates the L-type Ca ²⁺ channel Ca _V 1.2 and vasoconstriction during acute hyperglycemia and diabetes

Ser ¹⁹²⁸ phosphorylation by PKA stimulates the L-type Ca ²⁺ channel Ca _V 1.2 and vasoconstriction during acute hyperglycemia and diabetes