The role and behavior of voltage-gated calcium channels in ischemia/reperfusion

Ischemia/reperfusion (I/R) injury is a pathological condition that arises from the complex interplay of multifaceted mechanisms such as calcium imbalance, oxidative stress, mitochondrial dysfunction, and inflammatory processes. Voltage-gated calcium channels (VGCCs) play a critical role in this pathogenesis by regulating calcium influx into the cell, thereby initiating a cascade of detrimental intracellular events. During the ischemic phase, depletion of ATP reserves leads to the dysfunction of calcium transport systems; in the reperfusion phase, the stimulation of VGCCs by reactive oxygen species (ROS) intensifies intracellular calcium overload. This accumulation triggers the opening of mitochondrial permeability transition pores, amplifies ROS production, and activates cell death pathways such as apoptosis, necrosis, and ferroptosis. This comprehensive review explores the structural subtypes and physiological functions of VGCCs in detail while broadly investigating their behavior under I/R conditions across various organ systems, including the cardiovascular, neurological, renal, and reproductive systems. The review focuses on the distinct roles of L-, T-, N-, and R-type VGCCs and examines current findings on tissue- and isoform-specific pharmacological blockade strategies. Experimental studies demonstrating the protective effects of VGCC inhibitors-such as nimodipine, mibefradil, and SNX-111-are critically evaluated along with their translational limitations. By integrating up-to-date mechanistic insights with preclinical and early clinical data, this review highlights VGCCs as promising molecular targets for preventing I/R injury. Future therapeutic strategies should focus on isoform-specific targeting, time-dependent administration, and organ-directed formulations to enhance efficacy and safety.