Targeting P21-activated Kinase 1 for Development of a Novel Anti-arrhythmic Drug Class

Overview

Journal Philos Trans R Soc Lond B Biol Sci

Specialty Biology

Date 2023 May 1

PMID 37122206

Authors

Yu He

Alexander Grassam-Rowe

Ming Lei

James S H Bae

Affiliations

Soon will be listed here.

Abstract

Evidence accumulated over the past decade suggests that p21-activated kinase 1 (PAK1) is a critical cardiac-protective signalling molecule. The present article provides an updated review of recent findings regarding the role of PAK1 in maintaining normal cardiac electrophysiological function through its regulation of membrane and Ca clocks. We first overviewed the PAK1 activation mechanism. We then discussed recent updated results showing the action mechanisms of PAK1 signalling on Cav1.2/Cav1.3 (I)-mediated Ca entry, ryanodine receptor type 2-mediated sarcoplasmic reticulum (SR) Ca release, transcriptional regulation of SR Ca-ATPase 2a, Na/Ca exchangers, and Ca/calmodulin-dependent protein kinase II. Finally, we proposed a new and exciting route for developing a PAK1-based therapeutic strategy for cardiac arrhythmias. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

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References

Zhao Z, Manser E, Chen X, Chong C, Leung T, Lim L . A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1. Mol Cell Biol. 1998; 18(4):2153-63. PMC: 121452. DOI: 10.1128/MCB.18.4.2153. View

Koth A, Oliveira B, Parfitt G, Buonocore J, Barros D . Participation of group I p21-activated kinases in neuroplasticity. J Physiol Paris. 2014; 108(4-6):270-7. DOI: 10.1016/j.jphysparis.2014.08.007. View

Wang Y, Wang S, Lei M, Boyett M, Tsui H, Liu W . The p21-activated kinase 1 (Pak1) signalling pathway in cardiac disease: from mechanistic study to therapeutic exploration. Br J Pharmacol. 2017; 175(8):1362-1374. PMC: 5867015. DOI: 10.1111/bph.13872. View

Osterrieder W, Brum G, Hescheler J, TRAUTWEIN W, Flockerzi V, Hofmann F . Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current. Nature. 1982; 298(5874):576-8. DOI: 10.1038/298576a0. View

Tu H, Wigler M . Genetic evidence for Pak1 autoinhibition and its release by Cdc42. Mol Cell Biol. 1998; 19(1):602-11. PMC: 83918. DOI: 10.1128/MCB.19.1.602. View

Rettig M, Trinidad K, Pezeshkpour G, Frost P, Sharma S, Moatamed F . PAK1 kinase promotes cell motility and invasiveness through CRK-II serine phosphorylation in non-small cell lung cancer cells. PLoS One. 2012; 7(7):e42012. PMC: 3407072. DOI: 10.1371/journal.pone.0042012. View

Walweel K, Gomez-Hurtado N, Rebbeck R, Oo Y, Beard N, Molenaar P . Calmodulin inhibition of human RyR2 channels requires phosphorylation of RyR2-S2808 or RyR2-S2814. J Mol Cell Cardiol. 2019; 130:96-106. PMC: 6791359. DOI: 10.1016/j.yjmcc.2019.03.018. View

Sorrell F, Kilian L, Elkins J . Solution structures and biophysical analysis of full-length group A PAKs reveal they are monomeric and auto-inhibited in . Biochem J. 2019; 476(7):1037-1051. PMC: 6448136. DOI: 10.1042/BCJ20180867. View

Liu Q, Hofmann P . Antiadrenergic effects of adenosine A(1) receptor-mediated protein phosphatase 2a activation in the heart. Am J Physiol Heart Circ Physiol. 2002; 283(4):H1314-21. DOI: 10.1152/ajpheart.00343.2002. View

10.

Yeo D, He H, Patel O, Lowy A, Baldwin G, Nikfarjam M . FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine. BMC Cancer. 2016; 16:24. PMC: 4715347. DOI: 10.1186/s12885-016-2057-z. View

11.

Li J, Imtiaz M, Beard N, Dulhunty A, Thorne R, vanHelden D . ß-Adrenergic stimulation increases RyR2 activity via intracellular Ca2+ and Mg2+ regulation. PLoS One. 2013; 8(3):e58334. PMC: 3606165. DOI: 10.1371/journal.pone.0058334. View

12.

Wang J, Wu J, Wang Z . Structural insights into the autoactivation mechanism of p21-activated protein kinase. Structure. 2011; 19(12):1752-61. DOI: 10.1016/j.str.2011.10.013. View

13.

Terentyev D, Belevych A, Terentyeva R, Martin M, Malana G, Kuhn D . miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circ Res. 2009; 104(4):514-21. PMC: 4394868. DOI: 10.1161/CIRCRESAHA.108.181651. View

14.

Kumar R, Sanawar R, Li X, Li F . Structure, biochemistry, and biology of PAK kinases. Gene. 2016; 605:20-31. PMC: 5250584. DOI: 10.1016/j.gene.2016.12.014. View

15.

Carr A, Schmidt A, Suzuki Y, Monte F, Sato Y, Lanner C . Type 1 phosphatase, a negative regulator of cardiac function. Mol Cell Biol. 2002; 22(12):4124-35. PMC: 133876. DOI: 10.1128/MCB.22.12.4124-4135.2002. View

16.

Xiao B, Tian X, Xie W, Jones P, Cai S, Wang X . Functional consequence of protein kinase A-dependent phosphorylation of the cardiac ryanodine receptor: sensitization of store overload-induced Ca2+ release. J Biol Chem. 2007; 282(41):30256-64. DOI: 10.1074/jbc.M703510200. View

17.

Wang Y, Tsui H, Ke Y, Shi Y, Li Y, Davies L . Pak1 is required to maintain ventricular Ca²⁺ homeostasis and electrophysiological stability through SERCA2a regulation in mice. Circ Arrhythm Electrophysiol. 2014; 7(5):938-48. PMC: 4213946. DOI: 10.1161/CIRCEP.113.001198. View

18.

Respress J, van Oort R, Li N, Rolim N, Dixit S, deAlmeida A . Role of RyR2 phosphorylation at S2814 during heart failure progression. Circ Res. 2012; 110(11):1474-83. PMC: 3371642. DOI: 10.1161/CIRCRESAHA.112.268094. View

19.

DeSantiago J, Bare D, Varma D, Solaro R, Arora R, Banach K . Loss of p21-activated kinase 1 (Pak1) promotes atrial arrhythmic activity. Heart Rhythm. 2018; 15(8):1233-1241. PMC: 7017889. DOI: 10.1016/j.hrthm.2018.03.041. View

20.

Ke Y, Sheehan K, Egom E, Lei M, Solaro R . Novel bradykinin signaling in adult rat cardiac myocytes through activation of p21-activated kinase. Am J Physiol Heart Circ Physiol. 2010; 298(4):H1283-9. PMC: 2853422. DOI: 10.1152/ajpheart.01070.2009. View