Table 7.
Selected ion channels that are transcriptionally and functionally changed in lung tissues, PASMCs and PAECs from patients with PAH (in vitro studies) and animals with experimental PH (animal studies)
| Category | Major Functional Effect | References |
|---|---|---|
| Ca2+ channels including VDCC (CaV), ROCC (TRP), SOCC (Orai), and intracellular channels | ||
| ↑CaV1.2 (L-type), ↑CaV3.2 (T-type) | ↑[Ca2+]cyt → ↑SMC contraction → vasoconstriction | (76, 110, 123, 131, 377–379, 387, 587–595) |
| ↑TRPC1/3/6, ↑TRPM6/7, ↑TRPV1/4 | ↑[Ca2+]cyt → cell migration and proliferation → vascular remodeling | |
| ↑Orai1/2-STIM1/2 | ↑Na+ influx → Em depolarization in SMC → ↑VDCC → ↑[Ca2+]cyt | |
| ↑IP3 receptor (IP3R1) | ↑IP3R/RyR → agonist- and Ca2+-induced Ca2+ release → ↑[Ca2+]cyt → ↑ SMC contraction/migration → vasoconstriction and vascular remodeling | |
| ↑Ryanodine receptor (RyR2) | ||
| K+ channels including KV (KCN), KCa (KCNM), and K2P (KCNK) channels | ||
| ↓KCNA1/2/4/5, ↓KCNB1, ↓KCNH2, ↓KCNQ4 | ↓K+ current → Em depolarization → ↑VDCC → ↑[Ca2+]cyt → ↑SMC contraction | (431, 448, 467, 472, 476, 484, 495, 500, 502, 503, 506, 583, 584, 587, 596–600) |
| ↑↓KCNMA1, ↑KCNMB1 | ↑K+ current → Em hyperpolarization and repolarization → ↓VDCC → ↓[Ca2+]cyt → SMC relaxation → vasodilation | |
| ↓KCNK3/KCNK6, ↓KCNK15/KCNK17 | ↑K+ efflux → ↑H2O leak → AVD → apoptosis | |
| ↑K+ efflux → ↓[K+]cyt→ ↑caspase activity → apoptosis | ||
| ↑K+ efflux → ↓[K+]cyt → ↑inflammasome activation and formation → vascular inflammation → vascular remodeling | ||
| Na+ channels including voltage-gated (SCN), acid-sensitive (ASIC), and epithelial (ENaC) Na+ channel | ||
| ↑SCN1A/SCN3A/SCN9A | ↑Na+ influx → Em depolarization in SMC → ↑Ca2+ influx → ↑[Ca2+]cyt → ↑SMC contraction/migration/proliferation → vasoconstriction and vascular remodeling | (517–519, 587, 601, 602) |
| ↑ASIC1/ASIC2/ASIC3 | ↓Na+ influx in epithelial cell → pulmonary edema | |
| ↓ENaC | ||
| Gap junction channels | ||
| ↑Cx37 in EC | ↑Cx37 in EC → ↑lung endothelial injury → vascular remodeling | (283, 304, 308, 309, 319, 321, 322) |
| ↓↑Cx40 in EC | ↓Cx40 in EC → ↓endothelium-dependent relaxation → vasoconstriction | |
| ↑Cx43 in SMC | ↑Cx40 in EC → ↑Em depolarization from EC to SMC → HPV | |
| ↑Cx43 in SMC → ↑SMC proliferation → vascular remodeling | ||
| Cl− channels | ||
| ↑Ca2+-activated Cl− channel (TMEM16A) in SMC | ↑[Ca2+]cyt → ↑Cl− efflux → Em depolarization in SMC → ↑[Ca2+]cyt → SMC contraction/proliferation → vasoconstriction and vascular remodeling | (432, 434–442) |
| ↑CLIC4 → ↑ARF6 → ↓BMPRII → EC proliferation | ||
| ↑Intracellular Cl− channel (CLIC4) in EC and SMC | ↑CLIC4 → ↑ARF6 → ↑NF-kB → EC inflammation | |
| ↑CLIC4 → ↑RhoA/Rac1 → SMC migration/proliferation | ||
| Water channels (aquaporin) | ||
| ↑AQP1 | ↑β-catenin → ↑c-Myc/cyclin D1 → SMC migration/proliferation → vascular remodeling | (542, 545,546) |
↑increase, activate or upregulate; ↓decrease, inhibit, or downregulate. AVD, apoptotic volume decrease; ARF6, ADP ribosylation factor 6; BMPRII, bone morphogenetic protein receptor II; [Ca2+]cyt, cytosolic free Ca2+ concentration; EC, endothelial cell; Em, membrane potential; HPV, hypoxic pulmonary vasoconstriction; IP3, inositol (1,4,5)-trisphosphate; [K+]cyt, cytosolic free K+ concentration; KV, voltage-gated K+ channel; KCa, Ca2+-activated K+ channel; K2P, 2-pore domain K+ channel; PAEC. pulmonary arterial endothelial cell; PAH, pulmonary arterial hypertension; PASMC, pulmonary arterial smooth muscle cell; ROCC, receptor-operated cation channel; SMC, smooth muscle cell; SOCC, store-operated cation channel; VDCC, voltage-dependent Ca2+ channel.