Significance: Calcium ion (Ca2+)/calmodulin (CaM)-dependent protein kinases (CaMKs) are activated by phosphorylation of a crucial threonine residue either by itself (CaMKII) or by upstream kinases, CaMK kinases (CaMKKs) (CaMKI and CaMKIV). CaMKs, present in most mammalian tissues, can phosphorylate many downstream targets, thereby regulating numerous cellular functions. Recent Advances: Aside from canonical post-translational modifications, cysteine-based redox switches in CaMKs affect their enzyme activities. In addition to reactive oxygen species (ROS) and reactive nitrogen species (RNS), reactive sulfur species (RSS) are also recognized as key signaling molecules, regulating protein function through polysulfidation, formation of polysulfides [-S-(S)n-H] on their reactive cysteine residues. To comprehend the biological significance of RSS signaling-related CaMK regulation, here we introduce a novel concept defining CaMKs as RSS targets in stress responses. The stress responses include an irreversible electrophile attack for CaMKI, inflammation for CaMKII, and endoplasmic reticulum stress for CaMKIV. Critical Issues: Development of various human diseases is associated with increased ROS, RNS, and RSS generation. Therefore, depending on specific pathophysiology, RSS could have very particular effects on CaMK functions. Future Directions: How multiple sources and mutual reactions of ROS, RNS, and RSS are coordinated is obscure. Elucidating the mechanisms through applications of enzymology, chemical biology, and mass spectrometry enables to uncover the complexities of redox regulation of CaMK cascades.
Keywords: Ca2+/calmodulin-dependent protein kinase (CaMK); cysteine-based redox switches; phosphorylation; polysulfidation; reactive sulfur species (RSS).