Canonical Transient Potential Receptor-3 Channels in Normal and Diseased Airway Smooth Muscle Cells

All seven canonical transient potential receptor (TRPC1-7) channel members are expressed in mammalian airway smooth muscle cells (ASMCs). Among this family, TRPC3 channel plays an important role in the control of the resting [Ca²⁺]_i and agonist-induced increase in [Ca²⁺]_i. This channel is significantly upregulated in molecular expression and functional activity in airway diseases. The upregulated channel significantly augments the resting [Ca²⁺]_i and agonist-induced increase in [Ca²⁺]_i, thereby exerting a direct and essential effect in airway hyperresponsiveness. The increased TRPC3 channel-mediated Ca²⁺ signaling also results in the transcription factor nuclear factor-κB (NF-κB) activation via protein kinase C-α (PKCα)-dependent inhibitor of NFκB-α (IκBα) and calcineurin-dependent IκBβ signaling pathways, which upregulates cyclin-D1 expression and causes cell proliferation, leading to airway remodeling. TRPC3 channel may further interact with intracellular release Ca²⁺ channels, Orai channels and Ca²⁺-sensing stromal interaction molecules, mediating important cellular responses in ASMCs and the development of airway diseases.