This highlight article summarizes the current published literature of ion channels and ion transport in type I cells. Twenty years ago, the general theory of ion and fluid transport in the lung was that the alveolar type II cells, known to contain ion channels, governed ion transport and that the type I cells, believed to be incapable of ion transport, only allowed passive movement of water. Unable to reconcile the extraordinarily large surface area covered by type I cells (95% of the internal surface area of the lung) with such minimal biological activity, investigators set out to demonstrate that type I cells were capable of ion transport and played a role in regulating lung fluid balance. Various methods were employed to show that type I cells contained ENaC (HSC and NSC channels), CNG and K(+) channels, and CFTR, further necessitating a revision of the current theories of ion and fluid transport in the lung.

Fractionation of cytosolic sphingosine kinase (SKase) activity by gel filtration chromatography gave rise to a 96-kDa peak that contained only the SK2 form of SKase (by Western analysis) and a broad ca. 46 kDa peak that contained only SK1 forms. SK2 appeared to have a bound accessory protein. When tested with the classic SKase inhibitor dimethylsphingosine (DMS), SK1 was extensively inhibited; however, SK2 was not inhibited but unexpectedly was activated. Activation of SK2 was the result of DMS enhancing the affinity of the enzyme for sphingosine, and, at low concentrations of ATP and sphingosine, activated by more than 100%. Activation of SK2 could be demonstrated in the cytosolic fraction indicating it was unrelated to the purification step. The immunomodulator FTY720 also activated SK2 (although to a lesser extent), but was a potent inhibitor of SK1. SK2 from rat liver and spleen was also not inhibited by DMS. L-Sphingosine and to a lesser extent dihydrosphingosine and phytosphingosine were effective inhibitors of both forms.