Voltage-gated and store-operated calcium entry pathways (VGCC/SOCE)

Voltage-gated and store-operated calcium entry (SOCE) pathways are the primary mechanisms for regulating intracellular calcium (Ca2+) concentrations in airway smooth muscle (ASM) cells (PubMed: 28213294). Voltage-gated calcium channels (VGCCs), specifically the L-type channel (Cav1.2), allow Ca2+ influx upon membrane depolarization, which is a key step in excitation-contraction coupling (UniProt: Q13936). In contrast, the store-operated pathway is activated by the depletion of Ca2+ from the sarcoplasmic reticulum, sensed by STIM1, which then recruits and activates Orai1 channels on the plasma membrane (UniProt: Q13586, Q96D31). Together, these pathways maintain the Ca2+ homeostasis required for ASM tone and are significantly upregulated in inflammatory conditions like asthma and chronic obstructive pulmonary disease (COPD) (PubMed: 23821633). Dysregulation of these pathways leads to airway hyperresponsiveness and structural remodeling of the airways, making them attractive therapeutic targets. Pharmacological interventions include traditional calcium channel blockers like nifedipine and novel Orai1 inhibitors such as CM4620, which aim to reduce bronchoconstriction and inflammation (PubMed: 25633451). However, the ubiquitous nature of these channels poses challenges, as systemic inhibition can result in cardiovascular side effects or impaired immune cell function.

Other names

VGCC and SOCE pathwaysCalcium entry in airway smooth muscleASM calcium signalingL-type calcium channels and Orai1/STIM1 complex

Inhibition of L-type voltage-gated calcium channels (VGCCs) and/or blockade of Orai1-mediated store-operated calcium entry (SOCE) to reduce intracellular calcium levels and airway smooth muscle tone.