The cardiac L‐type calcium channel alpha subunit is a target for direct redox modification during oxidative stress—the role of cysteine residues in the alpha interacting domain

Abstract

SummaryCardiovascular disease is the leading cause of death in the Western world. The incidence of cardiovascular disease is predicted to further rise with the increase in obesity and diabetes and with the aging population. Even though the survival rate from ischaemic heart disease has improved over the past 30 years, many patients progress to a chronic pathological condition, known as cardiac hypertrophy that is associated with an increase in morbidity and mortality. Reactive oxygen species (ROS) and calcium play an essential role in mediating cardiac hypertrophy. The L-type calcium channel is the main route for calcium influx into cardiac myocytes. There is now good evidence for a direct role for the L-type calcium channel in the development of cardiac hypertrophy. Cysteines on the channel are targets for redox modification and glutathionylation of the channel can modulate the function of the channel protein leading to the onset of pathology. The cysteine responsible for modification of L-type calcium channel function has now been identified. Detailed understanding of the role of cysteines as possible targets during oxidative stress may assist in designing therapy to prevent the development of hypertrophy and heart failure. K E Y W O R D SCav1.2 protein, cysteine, glutathionylation, heart, hypertrophy, L-type calcium channel, oxidative stress, structure-function relationship

Rotenone-induced inner retinal degeneration via presynaptic activation of voltage-dependent sodium and L-type calcium channels in rats

“…In the retina, voltage-dependent sodium and L-type calcium channels primarily regulate sodium and calcium entry into synaptic terminals, respectively 37,38 . Oxidative stress activates these voltage-dependent channels directly and/or indirectly via inhibition of sodium-potassium ATPase [39][40][41][42] . Furthermore, it is well-documented that rotenone increases intracellular calcium concentrations via activation of L-type voltage-dependent calcium channels in neuronal cells [43][44][45][46] .…”

Metabolic Alterations in Cardiomyocytes of Patients with Duchenne and Becker Muscular Dystrophies

“…Another potential source of L-type Ca 2+ currents alterations in dystrophic cardiomyocytes is the redox modification of the Cav1.2 alpha1 subunit (cysteine 543 oxidation) during oxidative stress [64], which results in an increase in the channel-mediated Ca 2+ influx [63].…”

Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

“…Ca 2+ influx though voltage-dependent L-type Ca 2+ channels (LTCC) during action potential initiates Ca 2+ release from the sarcoplasmic reticulum (SR). The LTCC consists of the pore forming subunit α1c, and regulatory subunits α2/δ and β2 ( Muralidharan et al, 2017 ). C-terminus associated calmodulin (CaM) confers Ca 2+ -dependent inactivation of the channel ( Peterson et al, 1999 ; Zühlke et al, 1999 ).…”

“…Ca 2+ -dependent inactivation of LTCC can be lessened by CaMKII-phosphorylation, a process activated under oxidizing conditions ( Xie et al, 2009 ). In addition, evidence suggests that the Ca 2+ channel can be directly activated during oxidative stress, and Cysteine 543 of α1c subunit confers redox sensitivity ( Muralidharan et al, 2017 ; Wilson et al, 2018 ). Clusters of ≤10 channels are primarily localized in T-tubules in the sites of contact with junctional SR, i.e., dyads, opposing clusters of RyR2 Ca 2+ release channels ( Inoue and Bridge, 2003 ).…”