The CaMKII inhibitor KN93-calmodulin interaction and implications for calmodulin tuning of NaV1.5 and RyR2 function

Johnson, Christopher N.; Pattanayek, Rekha; Potet, F; Rebbeck, Robyn T.; Blackwell, Daniel J.; Nikolaienko, Roman; Sequeira, Vasco; Meur, Rémy Le; Radwański, Przemysław; Davis, Jonathan P.; Zima, Aleksey V.; Cornea, Rǎzvan L.; Damo, Steven M.; Györke, Sándor; George, Alfred L.; Knollmann, Björn C.

doi:10.1016/j.ceca.2019.102063

Cited by 38 publications

(37 citation statements)

References 57 publications

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“…To optimize myoplasmic Ca 2+ cycling for muscle performance, SERCA uptake activity must be fine-tuned in balance with Ca 2+ release activity via the SR Ca 2+ channel Ryanodine Receptor (RYR). The skeletal muscle isoform RYR1 is regulated by myoplasmic and luminal Ca 2+ levels, plus Ca 2+ -regulated proteins such as calsequestrin, calmodulin-dependent protein kinase, and calmodulin [ 29 , 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

Sarcolipin Exhibits Abundant RNA Transcription and Minimal Protein Expression in Horse Gluteal Muscle

Autry

Karim

Perumbakkam

et al. 2020

Veterinary Sciences

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Ca2+ regulation in equine muscle is important for horse performance, yet little is known about this species-specific regulation. We reported recently that horse encode unique gene and protein sequences for the sarcoplasmic reticulum (SR) Ca2+-transporting ATPase (SERCA) and the regulatory subunit sarcolipin (SLN). Here we quantified gene transcription and protein expression of SERCA and its inhibitory peptides in horse gluteus, as compared to commonly-studied rabbit skeletal muscle. RNA sequencing and protein immunoblotting determined that horse gluteus expresses the ATP2A1 gene (SERCA1) as the predominant SR Ca2+-ATPase isoform and the SLN gene as the most-abundant SERCA inhibitory peptide, as also found in rabbit skeletal muscle. Equine muscle expresses an insignificant level of phospholamban (PLN), another key SERCA inhibitory peptide expressed commonly in a variety of mammalian striated muscles. Surprisingly in horse, the RNA transcript ratio of SLN-to-ATP2A1 is an order of magnitude higher than in rabbit, while the corresponding protein expression ratio is an order of magnitude lower than in rabbit. Thus, SLN is not efficiently translated or maintained as a stable protein in horse muscle, suggesting a non-coding role for supra-abundant SLN mRNA. We propose that the lack of SLN and PLN inhibition of SERCA activity in equine muscle is an evolutionary adaptation that potentiates Ca2+ cycling and muscle contractility in a prey species domestically selected for speed.

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Section: Introductionmentioning

confidence: 99%

Sarcolipin Exhibits Abundant RNA Transcription and Minimal Protein Expression in Horse Gluteal Muscle

Autry

Karim

Perumbakkam

et al. 2020

Veterinary Sciences

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“…These results confirmed the functions of HSF1 as a master factor regulating the HSR in zebrafish. Inhibiting Ca 2+ channels by LaCl 3 and capsazepine ( Figure 6 B), and treatment with CaMKII inhibitor KN93 phosphate [ 44 ] ( Figure 6 C) also significantly decreased the expressions of the hsp genes. These results confirmed the functions of the Ca 2+ -CaMKII-HSF1 pathway in regulating the HSR of zebrafish larvae.…”

Section: Resultsmentioning

confidence: 99%

Generation of GCaMP6s-Expressing Zebrafish to Monitor Spatiotemporal Dynamics of Calcium Signaling Elicited by Heat Stress

Long

Xie

et al. 2021

IJMS

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The ability of organisms to quickly sense and transduce signals of environmental stresses is critical for their survival. Ca2+ is a versatile intracellular messenger involved in sensing a wide variety of stresses and regulating the subsequent cellular responses. So far, our understanding for calcium signaling was mostly obtained from ex vivo tissues and cultured cell lines, and the in vivo spatiotemporal dynamics of stress-triggered calcium signaling in a vertebrate remains to be characterized. Here, we describe the generation and characterization of a transgenic zebrafish line with ubiquitous expression of GCaMP6s, a genetically encoded calcium indicator (GECI). We developed a method to investigate the spatiotemporal patterns of Ca2+ events induced by heat stress. Exposure to heat stress elicited immediate and transient calcium signaling in developing zebrafish. Cells extensively distributed in the integument of the head and body trunk were the first batch of responders and different cell populations demonstrated distinct response patterns upon heat stress. Activity of the heat stress-induced calcium signaling peaked at 30 sec and swiftly decreased to near the basal level at 120 sec after the beginning of exposure. Inhibition of the heat-induced calcium signaling by LaCl3 and capsazepine and treatment with the inhibitors for CaMKII (Ca²⁺/calmodulin-dependent protein kinase II) and HSF1 (Heat shock factor 1) all significantly depressed the enhanced heat shock response (HSR). Together, we delineated the spatiotemporal dynamics of heat-induced calcium signaling and confirmed functions of the Ca2+-CaMKII-HSF1 pathway in regulating the HSR in zebrafish.

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“…It is also an attenuator of Ca 2+ -leak in a diabetes model of GlcNAcase inhibition (Erickson et al, 2013) and myocardial hypertrophy. Another study shows the high capacity to inhibit the binding of CaM with Na V 1.5, increasing the calcium release from RYR2 in cardiomyocytes independent from CamKII (Johnson et al, 2019). This suggests that KN-93 has interactions with the CaM-Ca 2+ binding; however, to inhibit CaMKII specifically, more affinized compound is necessary.…”

Section: Camkii Inhibition Displays Cardioprotectionmentioning

confidence: 99%

An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome

et al. 2020

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Calcium/calmodulin-dependent protein kinases (CaMKs) are key regulators of calcium signaling in health and disease. CaMKII is the most abundant isoform in the heart; although classically described as a regulator of excitation-contraction coupling, recent studies show that it can also mediate inflammation in cardiovascular diseases (CVDs). Among CVDs, cardiorenal syndrome (CRS) represents a pressing issue to be addressed, considering the growing incidence of kidney diseases worldwide. In this review, we aimed to discuss the role of CaMK as an inflammatory mediator in heart and kidney interaction by conducting an extensive literature review using the database PubMed. Here, we summarize the role and regulating mechanisms of CaMKII present in several quality studies, providing a better understanding for future investigations of CamKII in CVDs. Surprisingly, despite the obvious importance of CaMKII in the heart, very little is known about CaMKII in CRS. In conclusion, more studies are necessary to further understand the role of CaMKII in CRS.

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The CaMKII inhibitor KN93-calmodulin interaction and implications for calmodulin tuning of NaV1.5 and RyR2 function

Cited by 38 publications

References 57 publications

Sarcolipin Exhibits Abundant RNA Transcription and Minimal Protein Expression in Horse Gluteal Muscle

Sarcolipin Exhibits Abundant RNA Transcription and Minimal Protein Expression in Horse Gluteal Muscle

Generation of GCaMP6s-Expressing Zebrafish to Monitor Spatiotemporal Dynamics of Calcium Signaling Elicited by Heat Stress

An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome

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