The opening of several clustered ryanodine receptors (RyRs) in sarcoplasmic reticulum generates localized, short-lived Ca2+ transients, named Ca2+ sparks.In mouse airway smooth muscle (ASM), Ca2+ sparks activate big-conductance Ca2+-activated K+ channels to generate STOCs (spontaneous transient outward currents) and Ca2+-activated Cl-(ClCa) channels to produce STICs (spontaneous transient inward currents).The simultaneous activation of STOCs and STICs with different time courses results in membrane potential oscillations clamped within a negative range; this system prevents the ASM ceils from over-hyperpolarization or over-depolarization, thus keeping them at low excitability under physiological conditions.When either Ca2+ sparks or STOCs are blocked pharmacologically, ASM cells contract as a result of the activation of a positive feedback loop between ClCa channels and voltage-dependent Ca2+ channels.Deletion of Tmeml6a, a newly discovered gene for ClCa channels, abolishes STICs without affecting Ca2+ sparks, indicating that this gene encodes ClCa channels underlying STICs.Allergen sensitization and challenge in mice increase TMEM16A expression and the resulting airway hyperresponsiveness can be reversed by a ClCa channel blocker.Computer modeling with the biophysics ofTMEM16A ClCa channels and the [Ca2+] spatio-temporal profile derived from Ca2+ sparks reveals that the proximity between RyRs and TMEM16As is required for Ca2+ spark activation of STICs.Therefore, Ca2+ sparks and TMEM16As play important roles in ASM physiology and pathophysiology via local signaling.