Figure 1. Ion channels and their contribution to Ca²⁺ changes in airway smooth muscle cells.

The binding of agonist to its receptor activates phospholipase C (PLC) via membrane G-proteins to synthesize inositol trisphosphate (IP₃) and diacylglycerol (DAG) from membrane lipids. IP₃ (blue triangles) diffuses throughout the cell and binds to the IP₃R, sensitizing it to Ca²⁺, which stimulates the opening of the receptor to allow the release of Ca²⁺ from the sarcoplasmic reticulum (SR). The released Ca²⁺ in turn stimulates (+ black arrow) Ca²⁺-induced Ca²⁺ release from adjacent, sensitized IP₃Rs which results in the propagation of a Ca²⁺ wave. The released Ca²⁺ subsequently inactivates the IP₃R (− red arrow) and the Ca²⁺ is re- accumulated in the SR via Ca²⁺ pumps (SERCA). The repetitive release and uptake of Ca²⁺ results in Ca²⁺ oscillations. DAG and its derivatives (e.g. arachidonic acid, AA) move in the membrane to activate receptor-operated Ca²⁺ influx or channels (ROC) to replenish internal Ca²⁺ stores. During the Ca²⁺ oscillations, the Ca²⁺ store is partially depleted and this is sensed by STIM1 in the SR. STIM1 translocates through the SR membrane to aggregate with and activate store-operated Ca²⁺ entry or channels (SOC) (consisting of Orai1 or TRP proteins) to replenish the internal Ca²⁺ store. Ryanodine receptors (RyR) may release internal Ca²⁺ in the form of Ca²⁺ sparks to activate near by K_Ca channels to induce membrane hyperpolarization. K_Ca1.1 channels may be replaced with K_Ca3.1 channels during cell proliferation to alter membrane voltage which may influence voltage-dependent Ca²⁺ channels (VDC). Stretch-activated channels (SA) are directly gated by physical stimuli.