Targeting p21-activated kinase 1 for development of a novel anti-arrhythmic drug class

He, Yu; Grassam-Rowe, Alexander; Lei, Ming; Bae, James S. H.

doi:10.1098/rstb.2022.0285

Cited by 2 publications

(9 citation statements)

References 78 publications

(130 reference statements)

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“…PAK1 may be cardioprotective through increasing PP2A activity ( Ke et al, 2009 ; Wang et al, 2015 ) and its remodeling actions ( Liu et al, 2011 ; Wang et al, 2014 ; He et al, 2023 ; Jung et al, 2023 ). It may also modify Cav1.2/Cav1.3 ( I CaL )-mediated Ca 2+ entry, RyR2-mediated SR Ca 2+ release, and CaMKII-mediated SERCA2a and NCX transcriptional regulation ( He et al, 2023 ) and promote SERCA activity ( Ke et al, 2009 ; Wang et al, 2014 ; Wang et al, 2015 ). PAK1 deficiency may promote atrial arrhythmogenesis under adrenergic stress conditions through posttranslational and transcriptional modifications of key molecules including RyR2 and CaMKII ( Jung et al, 2023 ).…”

Section: Autonomic Feedforward and Feedbackmentioning

confidence: 99%

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Lei,

Salvage,

Jackson

et al. 2024

Front. Physiol.

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Cardiac arrhythmias cause significant morbidity and mortality and pose a major public health problem. They arise from disruptions in the normally orderly propagation of cardiac electrophysiological activation and recovery through successive cardiomyocytes in the heart. They reflect abnormalities in automaticity, initiation, conduction, or recovery in cardiomyocyte excitation. The latter properties are dependent on surface membrane electrophysiological mechanisms underlying the cardiac action potential. Their disruption results from spatial or temporal instabilities and heterogeneities in the generation and propagation of cellular excitation. These arise from abnormal function in their underlying surface membrane, ion channels, and transporters, as well as the interactions between them. The latter, in turn, form common regulatory targets for the hierarchical network of diverse signaling mechanisms reviewed here. In addition to direct molecular-level pharmacological or physiological actions on these surface membrane biomolecules, accessory, adhesion, signal transduction, and cytoskeletal anchoring proteins modify both their properties and localization. At the cellular level of excitation–contraction coupling processes, Ca2+ homeostatic and phosphorylation processes affect channel activity and membrane excitability directly or through intermediate signaling. Systems-level autonomic cellular signaling exerts both acute channel and longer-term actions on channel expression. Further upstream intermediaries from metabolic changes modulate the channels both themselves and through modifying Ca2+ homeostasis. Finally, longer-term organ-level inflammatory and structural changes, such as fibrotic and hypertrophic remodeling, similarly can influence all these physiological processes with potential pro-arrhythmic consequences. These normal physiological processes may target either individual or groups of ionic channel species and alter with particular pathological conditions. They are also potentially alterable by direct pharmacological action, or effects on longer-term targets modifying protein or cofactor structure, expression, or localization. Their participating specific biomolecules, often clarified in experimental genetically modified models, thus constitute potential therapeutic targets. The insights clarified by the physiological and pharmacological framework outlined here provide a basis for a recent modernized drug classification. Together, they offer a translational framework for current drug understanding. This would facilitate future mechanistically directed therapeutic advances, for which a number of examples are considered here. The latter are potentially useful for treating cardiac, in particular arrhythmic, disease.

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Section: Autonomic Feedforward and Feedbackmentioning

confidence: 99%

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Lei,

Salvage,

Jackson

et al. 2024

Front. Physiol.

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“…[ 27 ] and He et al . [ 28 ] review subsequent findings emerging from such genetic platforms; Anderson et al . [ 29 ] implicate circadian variations in sympathetic actions on pacemaker ion channel gene transcription in diurnal cardiac rate variations in wild-type (WT) murine hearts.…”

Section: Modern Developments In the Fieldmentioning

confidence: 99%

“…The cardioprotective effects of Pak1 may thus involve increased PP2A activity [ 101 , 102 ] additional to its potentially strategic remodelling actions [ 103 , 104 ] discussed in §9 (He et al . [ 28 ]; Jung et al . [ 27 ]) .…”

Section: Autonomic G-protein-mediated Modulationmentioning

confidence: 99%

“…He et al . [ 28 ] review one line of investigation exploring possible protective signalling actions of PAK1 possibly through altering Cav1.2/Cav1.3 ( I CaL )-mediated Ca 2+ entry, RyR2-mediated SR Ca 2+ release and CaMKII-mediated transcriptional regulation of SERCA2a and NCX. Conversely, Jung et al .…”

Section: Cardiac Remodelling and Excitable Propertiesmentioning

confidence: 99%

“…Thus, the key cardiomyocyte regulator of ion channel activity, Ca 2+ homeostasis and cardiac contractility [ 101 , 102 , 105 ], PAK1 may offer cardioprotective actions through inhibiting maladaptive, pro-arrhythmic, hypertrophic remodelling and progression in cardiac failure [ 187 , 188 ], actions of possible therapeutic utility (He et al . [ 28 ]; see also §§6 and 7).…”

Section: Cardiac Remodelling and Excitable Propertiesmentioning

confidence: 99%

See 2 more Smart Citations

Cardiomyocyte electrophysiology and its modulation: current views and future prospects

Huang

Lei

2023

Phil. Trans. R. Soc. B

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Normal and abnormal cardiac rhythms are of key physiological and clinical interest. This introductory article begins from Sylvio Weidmann's key historic 1950s microelectrode measurements of cardiac electrophysiological activity and Singh & Vaughan Williams's classification of cardiotropic targets. It then proceeds to introduce the insights into cardiomyocyte function and its regulation that subsequently emerged and their therapeutic implications. We recapitulate the resulting view that surface membrane electrophysiological events underlying cardiac excitation and its initiation, conduction and recovery constitute the final common path for the cellular mechanisms that impinge upon this normal or abnormal cardiac electrophysiological activity. We then consider progress in the more recently characterized successive regulatory hierarchies involving Ca 2+ homeostasis, excitation–contraction coupling and autonomic G-protein signalling and their often reciprocal interactions with the surface membrane events, and their circadian rhythms. Then follow accounts of longer-term upstream modulation processes involving altered channel expression, cardiomyocyte energetics and hypertrophic and fibrotic cardiac remodelling. Consideration of these developments introduces each of the articles in this Phil. Trans. B theme issue. The findings contained in these articles translate naturally into recent classifications of cardiac electrophysiological targets and drug actions, thereby encouraging future iterations of experimental cardiac electrophysiological discovery, and testing directed towards clinical management. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

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Targeting p21-activated kinase 1 for development of a novel anti-arrhythmic drug class

Cited by 2 publications

References 78 publications

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Cardiomyocyte electrophysiology and its modulation: current views and future prospects

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