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Last update 08 May 2025

CAMK2N2

Last update 08 May 2025

Basic Info

Synonyms

calcium/calmodulin dependent protein kinase II inhibitor 2, Calcium/calmodulin-dependent protein kinase II inhibitor 2, CaM-KII inhibitory protein

+ [2]

Introduction

Potent and specific cellular inhibitor of CaM-kinase II (CAMK2) (PubMed:11444830). Traps Ca(2+)/calmodulin on CAMK2 (By similarity).

Drugs associated with CAMK2N2

KS-501

Target

CAMK2N2

Mechanism

CAMK2N2 inhibitors

Active Org.-

Originator Org.

Kyowa Hakko Kogyo Co., Ltd.

Active Indication-

Inactive Indication

Thromboembolism

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CAMK2N2

100 Translational Medicine associated with CAMK2N2

0 Patents (Medical) associated with CAMK2N2

120

Literatures (Medical) associated with CAMK2N2

01 May 2025·Phytomedicine

Stachydrine hydrochloride reduces NOX2 activity to suppress oxidative stress levels to improve cardiac insufficiency

Article

Author: Chen, Huihua ; Xu, Ming ; Lu, Rong ; Guo, Shuting ; Zhang, Chen ; Guo, Wei ; Shan, Xiaoli ; Fu, Mengwei ; Yang, Kaijing ; Li, Rongshan ; Zhao, Pei ; Yang, Songru

BACKGROUNDOxidative stress is a significant cause in the occurrence of cardiac insufficiency. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase2 (NOX2)-derived reactive oxygen species (ROS) play a pivotal role in oxidative stress-induced excitation-contraction decoupling. Stachydrine hydrochloride (Sta) reduces pressure overload-induced cardiac insufficiency, which may be related to the NOX2-ROS pathway, as demonstrated by our earlier research. However, the mechanism through which Sta specifically affects NOX2 remains unknown.PURPOSEIn order to investigate whether Sta plays a cardioprotective role by inhibiting NOX2 activity, we explored the specific mechanism by which Sta improves cardiac function by affecting NOX2-mediated oxidative stress in this study.METHODSMolecular docking and cellular thermal shift assay (CETSA) were performed to verify whether Sta can bind to individual subunits of NOX2. We induced models of cardiac insufficiency in the compensatory phase (cardiac hypertrophy) by phenylephrine (PE) in vivo and in vitro and treated with Sta and GSK2795039 (NOX2 inhibitor). Cardiac function and structure were observed by echocardiography analysis. We detected the expression and localization of NOX2 subunits and calcium channel proteins, also detected the activities of ROS and NOX2, SOD, and GSH, and observed intracardiac calcium homeostasis and systolic-diastolic function in cardiomyocytes. Secondly, we used adenovirus and adeno-associated virus transfection for cardiac-specific overexpression of NOX2 in vivo and in vitro respectively, and also treated with Sta to observe NOX2 activation indexes and ROS levels, cardiac function and cardiomyocyte function in mice.RESULTSPrior to our investigation, we discovered that Sta could bind to NOX2 through molecular docking and CETSA. The findings demonstrated that Sta decreased the expression levels of gp91^phox and p67^phox, as well as the phosphorylation levels of p47^phox, and by preventing p67^phox and p47^phox from translocating across cell membranes. NOX2 activity inhibition by Sta suppresses ROS production. Sta reduced ROS-induced oxidation of Ca²⁺/calmodulin protein kinase II and modulated excitatory-contractile coupling via sarcoplasmic reticulum calcium pumps. Cardiac-specific overexpression of gp91^phox promotes membrane translocation of p67^phox and p47^phox, increases NOX2 activity, and promotes ROS generation. Sta inhibition of gp91^phox overexpression reduced the membrane translocation of p67^phox and p47^phox, decreased NOX2 activity and oxidative stress levels, and restored excitatory-contractor-coupled myocardial function.CONCLUSIONSOur study innovatively verified the key role of NOX2 in cardiac insufficiency. Sta downgrades NOX2's activity by suppressing the protein level of gp91^phox and the membrane transport of p67^phox and p47^phox, thereby reducing myocardial oxidative stress and playing a cardioprotective role. This study was hoped to support the possibility of Sta as a cardiac function-enhancing drug in the future.

01 Jan 2025·Journal of Advanced Research

Astragaloside IV ameliorates autism-like behaviors in BTBR mice by modulating Camk2n2-dependent OXPHOS and neurotransmission in the mPFC

Article

Author: Chen, Mei ; Li, Xin ; Fan, Xiaotang ; Gong, Hong ; Liu, Tianyao ; Luo, Yi ; Shi, Jiahui ; Liu, Yulong ; Liu, Jiayin ; Luo, Jing ; Li, Jianghui

INTRODUCTIONAutism spectrum disorder (ASD) represents a multifaceted set of neurodevelopmental conditions marked by social deficits and repetitive behaviors. Astragaloside IV (ASIV), a natural compound derived from the traditional Chinese herb Astragali Radix, exhibits robust neuroprotective effects. However, whether ASIV can ameliorate behavioral deficits in ASD remains unknown.OBJECTIVESThis work aimed to determine the efficacy and molecular mechanisms of ASIV in ASD.METHODSThe autistic BTBR T + tf/J (BTBR) mice were used in this study. Behavioral tests were performed to assess the ASD-like phenotypes. The neurotransmitter levels and synaptic transmission were evaluated by high-performance liquid chromatography and whole-cell patch clamp recordings, respectively. Molecular biological techniques, immunostaining, and RNA-sequencing (RNA-seq) were combined to uncover the underlying molecular mechanisms.RESULTSOur study showed that both social impairment and repetitive behaviors were significantly improved after ASIV treatment in a dose-dependent manner in BTBR mice. The ASIV treatment normalized the neurotransmitter levels (GABA and glutamate) and their corresponding vesicular transporters (vGAT, vGLUT1) in the medial prefrontal cortex (mPFC). Furthermore, the excitation-inhibition imbalance in layer V of mPFC was reversed after ASIV administration. Mechanistically, bulk RNA-seq and PPI network analysis identified Camk2n2 as the crucial bridging gene regulating oxidative phosphorylation and neurotransmission. Camk2n2 overexpression in the mPFC abolished the beneficial effects of ASIV on autistic symptoms in BTBR mice via the Camk2/CREB pathway.CONCLUSIONThe evidence demonstrates that ASIV may become a promising treatment option for ASD and implies that targeting the Camk2n2/Camk2/CREB axis is warranted to investigate these ASD individuals further.

01 Nov 2024·European Journal of Pharmacology

ML218 modulates calcium binding protein, oxidative stress, and inflammation during ischemia-reperfusion brain injury in mice

Article

Author: Ghildiyal, Shivani ; Sharma, Bhupesh ; Sharma, Poonam ; Kharkwal, Harsha

Cerebral ischemia disrupts calcium homeostasis in the brain causing excitotoxicity, oxidative stress, inflammation, and neuronal cell apoptosis. During ischemic conditions, T-type calcium channel channels contribute to increase in intracellular calcium ions in both neurons and glial cells therefore, the current study hypothesizes the antagonism of these channels using ML218, a novel specific T-Type inhibitor in experimental model of cerebral ischemia-reperfusion (CI/R) brain injury. CI/R injury was induced in Swiss Albino mice by occlusion of common carotid arteries followed by reperfusion. Animals were assessed for learning and memory (MWM), motor coordination (Rota rod), neurological function (neurological deficit score), cerebral infarction, edema, and histopathological alterations. Biochemical assessments were made for calcium binding proteins (Calmodulin- CaM, calcium/calmodulin-dependent protein kinase II-CaMKII, S100B), oxidative stress (4-hydroxy 2-nonenal-4-HNE, glutathione-GSH, inflammation (nuclear factor kappa-light-chain-enhancer of activated B-p65-NF-kB, tumor necrosis factor-TNF-α, interleukin-IL-10) inducible nitric oxide synthase (iNOS) levels, and acetylcholinesterase activity (AChE) in brain supernatants. Furthermore, serum levels of NF-kB, iNOS, and S100B were also assessed. CI/R animals showed impairment in learning, memory, motor coordination, and neurological function along with increase in cerebral infarction, edema, and histopathological alterations. Furthermore, increase in brain calcium binding proteins, oxidative stress, inflammation, and AChE activity along with serum NF-kB, iNOS, and S100B levels were recorded in CI/R animals. Administration of ML218 (5 mg/kg and 10 mg/kg; i.p.) was observed to recuperate CI/R induced impairments in behavioral, biochemical, and histopathological analysis. Hence, it may be concluded that ML218 mediates neuroprotection during CI/R via decreasing brain and serum calcium binding proteins, inflammation, iNOS, and oxidative stress markers.

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CAMK2N2

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