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

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 Ca²⁺ 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_CaL)-mediated Ca²⁺ entry, ryanodine receptor type 2-mediated sarcoplasmic reticulum (SR) Ca²⁺ release, transcriptional regulation of SR Ca²⁺-ATPase 2a, Na⁺/Ca²⁺ exchangers, and Ca²⁺/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'.

Keywords: Ca2+ clock; FTY720; arrhythmia; membrane clock; p21-activated kinase 1; protein phosphatase 2A.