Calcium channels in anesthesia management: A molecular and clinical review

Abstract

Calcium channels play an essential role in the molecular and physiological mechanisms underlying anesthesia by mediating intracellular calcium ion (Ca²⁺) flux, which regulates key processes such as neurotransmitter release, neuronal excitability, and immune responses. Voltage-gated calcium channels (VGCCs) and ligand-gated calcium channels (LGCCs) are integral to the anesthetic process, with subtypes such as T-type VGCCs and NMDA receptors influencing consciousness and pain perception. This review emphasizes current evidence to highlight how anesthetic agents interact with calcium channels via direct inhibition and modulation of intracellular signaling pathways, such as phosphatidylinositol metabolism. Additionally, calcium channelopathies - genetic or acquired dysfunctions affecting VGCCs and LGCCs - pose challenges in anesthetic management, including arrhythmias, malignant hyperthermia, and altered anesthetic sensitivity. These findings underscore the critical need for precision medicine approaches tailored to patients with these conditions. While significant progress has been made in understanding the roles of calcium channels in anesthesia, knowledge gaps remain regarding the long-term implications of anesthetic interactions on calcium signaling and clinical outcomes. This review bridges foundational science with clinical practice, emphasizing the translational potential of calcium channel research for optimizing anesthetic strategies. By integrating molecular insights with emerging pharmacogenomic approaches, it provides a pathway for developing safer and more effective anesthesia protocols that enhance patient outcomes.

Keywords: Anesthesia; anesthetic mechanisms; calcium channelopathies; calcium channels.

Figure 1.

Schematic representation of action potential generation and propagation in the presynaptic neuron, illustrating the vital role of voltage-gated calcium channels (VGCCs) in neurotransmitter release and the modulatory effects of anesthetics. Upon arrival of the action potential at the presynaptic terminal, VGCCs open and permit calcium influx, triggering synaptic vesicle fusion and neurotransmitter release into the synaptic cleft. These neurotransmitters subsequently bind to postsynaptic receptors, eliciting a cellular response. By blocking or modulating VGCCs and other ion channels, anesthetics diminish neurotransmitter release and attenuate synaptic transmission, thereby exerting their anesthetic effect (The figure was drown by Biorender).

Figure 2.

Schematic representation of synaptic transmission and the modulatory effects of anesthetics. Upon arrival of an action potential at the presynaptic terminal, voltage-gated calcium channels (VGCC) open, allowing Ca²⁺ influx and triggering the release of neurotransmitters (e.g. acetylcholine, glutamate, GABA, glycine). These neurotransmitters then bind to ionotropic receptors on the postsynaptic membrane, leading to the opening of either cation channels (Na⁺, K⁺, Ca²⁺) and subsequent depolarization (excitatory response), or Cl⁻ channels and hyperpolarization (inhibitory response). Anesthetics can influence both presynaptic Ca²⁺ dynamics and postsynaptic receptor function, thereby modulating synaptic efficacy and overall neuronal excitability (The figure was drown by Biorender).

Figure 3.

Schematic overview of the pathophysiological mechanism underlying malignant hyperthermia. In individuals harboring mutations in the ryanodine receptor type 1 (RyR1), exposure to triggering agents (e.g. volatile anesthetics or succinylcholine) leads to aberrant calcium (Ca²⁺) release from the sarcoplasmic reticulum into the skeletal muscle cytoplasm. This excessive intracellular Ca²⁺ promotes sustained muscle contraction, resulting in muscle rigidity and marked heat production. The figure illustrates how succinylcholine acts on nicotinic acetylcholine receptors (nAChRs), facilitating ion flux (Na⁺ influx and K⁺ efflux), while volatile anesthetics can also potentiate RyR1 dysfunction. The uncontrolled rise in cytosolic Ca²⁺ initiates a hypermetabolic crisis, characterized by elevated CO₂ production, acidosis, and potential multi-organ compromise if not rapidly treated (The figure was drown by Biorender).