Receptor Species-dependent Desensitization Controls KCNQ1/KCNE1 K+ Channels as Downstream Effectors of Gq Protein-coupled Receptors

Kienitz, Marie-Cécile; Vladimirova, Dilyana; Müller, Christian; Pott, Lutz; Rinne, Andreas

doi:10.1074/jbc.m116.746974

Cited by 8 publications

(3 citation statements)

References 45 publications

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“…Without simultaneous tests for desensitization or for large continued Ins(1,4,5) P 3 and DAG production, it would be hard to interpret many isolated records in the literature. Compared with, for example, α 1B adrenergic receptors, M 1 muscarinic receptors are slow to desensitize ( Kienitz et al, 2016 ). We have found before that although M 1 muscarinic receptors do bind β-arrestin-2 to ∼50% occupancy, they are not internalized during a 10-min stimulation ( Jung et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 4,5-bisphosphate is regenerated by speeding of the PI 4-kinase pathway during long PLC activation

Myeong

Cruz

Jung

et al. 2020

Journal of General Physiology

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The dynamic metabolism of membrane phosphoinositide lipids involves several cellular compartments including the ER, Golgi, and plasma membrane. There are cycles of phosphorylation and dephosphorylation and of synthesis, transfer, and breakdown. The simplified phosphoinositide cycle comprises synthesis of phosphatidylinositol in the ER, transport, and phosphorylation in the Golgi and plasma membranes to generate phosphatidylinositol 4,5-bisphosphate, followed by receptor-stimulated hydrolysis in the plasma membrane and return of the components to the ER for reassembly. Using probes for specific lipid species, we have followed and analyzed the kinetics of several of these events during stimulation of M1 muscarinic receptors coupled to the G-protein Gq. We show that during long continued agonist action, polyphosphorylated inositol lipids are initially depleted but then regenerate while agonist is still present. Experiments and kinetic modeling reveal that the regeneration results from gradual but massive up-regulation of PI 4-kinase pathways rather than from desensitization of receptors. Golgi pools of phosphatidylinositol 4-phosphate and the lipid kinase PI4KIIIα (PI4KA) contribute to this homeostatic regeneration. This powerful acceleration, which may be at the level of enzyme activity or of precursor and product delivery, reveals strong regulatory controls in the phosphoinositide cycle.

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Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 4,5-bisphosphate is regenerated by speeding of the PI 4-kinase pathway during long PLC activation

Myeong

Cruz

Jung

et al. 2020

Journal of General Physiology

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“…On the other hand, the PIP 2 availability is regulated by stimulation of a G q/11 protein‐coupled receptor, whereby activated phospholipase Cβ hydrolyzes PIP 2 into soluble inositol 1,4,5‐trisphosphate and membrane‐bound diacylglycerol (Delmas & Brown, 2005). Acute activation of α1‐adrenergic receptors has been demonstrated to reduce I Ks through a cellular depletion of PIP 2 (Kienitz et al, 2016; Tobelaim et al, 2017). However, it remains unknown whether other major signaling pathways that have significant effects on cardiac myocytes, modulate PIP 2 regulation of I Ks .…”

Section: Introductionmentioning

confidence: 99%

Modulation of I_Ks channel–PIP₂ interaction by PRMT1 plays a critical role in the control of cardiac repolarization

Lee

Kim

et al. 2022

Journal Cellular Physiology

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Recent studies have shown that protein arginine methyltransferase 1 (PRMT1) is highly expressed in the human heart, and loss of PRMT1 contributes to cardiac remodeling in the heart failure. However, the functional importance of PRMT1 in cardiac ion channels remains uncertain. The slow activating delayed rectifier K+ (IKs) channel is a cardiac K+ channel composed of KCNQ1 and KCNE1 subunits and is a new therapeutic target for treating lethal arrhythmias in many cardiac pathologies, especially heart failure. Here, we demonstrate that PRMT1 is a critical regulator of the IKs channel and cardiac rhythm. In the guinea pig ventricular myocytes, treatment with furamidine, a PRMT1‐specific inhibitor, prolonged the action potential duration (APD). We further show that this APD prolongation was attributable to IKs reduction. In HEK293T cells expressing human KCNQ1 and KCNE1, inhibiting PRMT1 via furamidine reduced IKs and concurrently decreased the arginine methylation of KCNQ1, a pore‐forming α‐subunit. Evidence presented here indicates that furamidine decreased IKs mainly by lowering the affinity of IKs channels for the membrane phospholipid, phosphatidylinositol 4,5‐bisphosphate (PIP2), which is crucial for pore opening. Finally, applying exogenous PIP2 to cardiomyocytes prevented the furamidine‐induced IKs reduction and APD prolongation. Taken together, these results indicate that PRMT1 positively regulated IKs activity through channel–PIP2 interaction, thereby restricting excessive cardiac action potential.

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“…While such a resynthesis is essential in maintaining PIP2, especially against the fast rate of Gq-GPCR mediated PIP2 hydrolysis [21], the regulation of this PIP2 regeneration (recovery) is unclear [21,22]. Specifically, it is not clear if the initial PIP2 hydrolysis triggers this PIP2 recovery process [25][26][27] IP3 generated after PIP2 hydrolysis activates IP3 receptors and induces stored calcium release [28,29]. To maintain resting Ca 2+ concentrations, PM and Sarcoplasmic reticulum Ca 2+ ATPase pumps remove Ca 2+ from the cytosol.…”

Section: Introductionmentioning

confidence: 99%

G protein αq exerts expression level-dependent distinct signaling paradigms

Kankanamge

Tennakoon

Weerasinghe

et al. 2019

Cellular Signalling

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G protein αq-coupled receptors (Gq-GPCRs) primarily signal through GαqGTP mediated phospholipase Cβ (PLCβ) stimulation and the subsequent hydrolysis of phosphatidylinositol 4, 5 bisphosphate (PIP2). Though Gq-heterotrimer activation results in both GαqGTP and Gβγ. unlike Gi/o-receptors, it is unclear if Gq-coupled receptors employ Gβγ as a major signal transducer. Compared to Gi/o-and Gs-coupled receptors, we observed that most cell types exhibit a limited free Gβγ generation upon Gq-pathway and Gαq/11 heterotrimer activation. We show that cells transfected with Gαq or endogenously expressing more than average-levels of Gαq/11 compared to Gαs and Gαi exhibit a distinct signaling regime primarily characterized by recovery-resistant PIP2 hydrolysis. Interestingly, the elevated Gq-expression is also associated with enhanced free Gβγ generation and signaling. Furthermore, the gene GNAQ, which encodes for Gαq, has recently been identified as a cancer driver gene. We also show that GNAQ is overexpressed in tumor samples of patients with Kidney Chromophobe (KICH) and Kidney renal papillary (KIRP) cell carcinomas in a matched tumor-normal sample analysis, which demonstrates the clinical significance of Gαq expression. Overall, our data indicates that cells usually express low Gαq levels, likely safeguarding cells from excessive calcium as wells as from Gβγ signaling.

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Receptor Species-dependent Desensitization Controls KCNQ1/KCNE1 K+ Channels as Downstream Effectors of Gq Protein-coupled Receptors

Cited by 8 publications

References 45 publications

Phosphatidylinositol 4,5-bisphosphate is regenerated by speeding of the PI 4-kinase pathway during long PLC activation

Phosphatidylinositol 4,5-bisphosphate is regenerated by speeding of the PI 4-kinase pathway during long PLC activation

Modulation of I_Ks channel–PIP₂ interaction by PRMT1 plays a critical role in the control of cardiac repolarization

G protein αq exerts expression level-dependent distinct signaling paradigms

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Receptor Species-dependent Desensitization Controls KCNQ1/KCNE1 K+ Channels as Downstream Effectors of Gq Protein-coupled Receptors

Cited by 8 publications

References 45 publications

Phosphatidylinositol 4,5-bisphosphate is regenerated by speeding of the PI 4-kinase pathway during long PLC activation

Phosphatidylinositol 4,5-bisphosphate is regenerated by speeding of the PI 4-kinase pathway during long PLC activation

Modulation of IKs channel–PIP2 interaction by PRMT1 plays a critical role in the control of cardiac repolarization

G protein αq exerts expression level-dependent distinct signaling paradigms

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Modulation of I_Ks channel–PIP₂ interaction by PRMT1 plays a critical role in the control of cardiac repolarization