Fig. 2.

Regulation intracellular Ca²⁺ ([Ca²⁺]_i) in airway smooth muscle (ASM). While a number of mechanisms are well recognized, including agonist-induced production of the second messengers IP₃ (via the enzyme phospholipase C; PLC) and cyclic ADP ribose (cADPR) via the ectoenzyme CD38, leading to sarcoplasmic reticulum Ca²⁺ release from IP₃ receptor and ryanodine receptor channels, respectively, and Ca²⁺ influx through various types of channels, there are new regulatory pathways recently reported. For example, PLC can be upregulated by PKA and PKG but inhibited by flavanols and PDE4, while IP₃ can regulate Ca²⁺ sparks and influx through voltage-gated Ca²⁺ influx channels (VGCC). Calcineurin (usually associated with downstream transcription) can regulate RyR channels and in turn be regulated by TRP influx channels. Influx of extracellular Ca²⁺ ([Ca²⁺]_o) can occur through VGCCs, TRPC, and TRPV channels as well as reverse mode Na⁺/Ca²⁺ exchange (NCX). In terms of force sensitization involving RhoA, active RhoA levels can be regulated by RhoGAPs and RhoGEFs, an emerging area in ASM. CaCC, calcium-activated chloride channel; NAD, nicotinamide adenine dinucleotide; BKCa, big calcium-activated potassium channel; MLCP, myosin light chain phosphatase; IP3R, IP3 receptor; SERCA, sarcoendoplasmic reticulum calcium ATPase; SR, sarcoplasmic reticulum.