Basolateral potassium channels and epithelial ion transport.

The two-membrane hypothesis, proposed by KoefoedJohnsen and Ussing (1) in 1958, formalized the concepts that the inner and outer membranes of the frog-skin epithelium are functionally different and that both membranes participate in active sodium absorption. The model described the frog skin as a homogenous intracellular compartment bounded by an apical and basolateral membrane with different ion transport properties. The apical membrane is sodium conductive (sodium channels), and the basolateral membrane contains Na 1 ,K 1 –adenosine triphosphatase (ATPase) pumps and is potassium conductive (potassium channels) (Figure 1). Approximately 20 years later (2), a similar model was developed to explain Cl 2 secretion by the dogfish rectal gland (Figure 2). Important modifications included ( 1 ) addition of a basolateral membrane Cl 2 entry step, and ( 2 ) replacement of the apical membrane Na 1 channel by a cyclic adenosine monophosphate (cAMP)–activated Cl 2 channel. Again, the apical and basolateral cell membranes are functionally different, and both membranes participate in active Cl 2 secretion. Several years earlier, Olver and colleagues (3) showed that canine airway epithelium absorbed Na 1 and secreted Cl 2 . A model that incorporates each of the transport elements found in the frog skin and shark rectal gland can explain both sodium absorption and chloride secretion by the airway epithelium (4). A major impetus for the study of ion transport in nonrenal tissues is the desire to understand and treat secretory diarrheal diseases and cystic fibrosis (CF), disorders that result from abnormal salt and fluid secretion (5, 6). The discovery that CF is caused by the loss of an apical membrane, cAMP-activated Cl 2 conductance (7, 8), coupled with the knowledge that cholera toxin activates adenylate cyclase and stimulates intestinal secretion, focused attention on apical membrane Cl 2 channels in gastrointestinal and airway epithelia. The first epithelial ion channel to be identified and cloned was the CF transmembrane conductance regulator (CFTR) (9). Accordingly, we now know a great deal about the expression, regulation, and function of apical CFTR Cl 2 channels and their role in Cl 2 secretion (10). Several other Cl 2 channels have been cloned during the past decade, but the importance of the so-called ClC protein family members in epithelial Cl 2 secretion is uncertain (11). There are, however, other non-CFTR apical membrane Cl 2 channels that do participate in epithelial Cl 2 secretion, but the molecular identity and many of the details of regulation of these transport proteins are yet to be established (12, 13, 14). The sodium channel that is present in the apical membrane and that mediates amiloride-sensitive sodium absorption by frog skin, colon, airway, and numerous other epithelia was recently cloned and is known as ENaC (15). The molecular identity of the basolateral isoform of the Na 1 ,K 1 ,2Cl 2 cotransporter, responsible for accumulation of intracellular Cl 2 for secretion, is also known (16). The Na 1 ,K 1 -ATPase, located at the basolateral membrane of nearly all epithelial cells, is crucial for generating and maintaining appropriate intracellular activities of sodium and potassium. The molecular identity of Na 1 ,K 1 -ATPase, as well as detailed knowledge of the regulation and mechanism of transport by the pump, are well established (17). The transport models that describe sodium absorption and Cl 2 secretion (Figures 1 and 2, respectively) both include basolateral potassium channels; however, the molecular identity of the proteins (channels) responsible for basolateral potassium conductance in epithelial cells remains largely unknown. The basolateral K 1 conductance pathway is critical in both secretory and absorptive epithelia, and inhibition of basolateral K 1 conductance with nonselective K 1 channel blockers (e.g., barium) will reduce transepithelial transport. Basolateral K 1 channels recycle the potassium that enters the cell in exchange for sodium via the Na 1 ,K 1 ATPase (Figures 1 and 2) and also the potassium that enters the cell across the basolateral membrane coupled to Na 1 and Cl 2 (Figure 2) in Cl 2 -secreting epithelia. Not only do K 1 channels recycle potassium, but they contribute to the membrane potential of the cell, an important determinant of the electrochemical driving force for passive ion movement across the plasma membrane. In the two transport models depicted above, Na 1 influx and Cl 2 efflux are both driven in part by the electrical potential difference that exists across the apical membrane. Although it is not necessarily obvious, the apical and basolateral membranes in epithelia are electrically coupled by an intraepithelial current loop that arises due to the existence of a finite ionic conductance across the paracellular pathway (18). In other words, depolarization or hyperpolarization of the basolateral cell membrane will influence the opposite membrane and vice versa. It has long been argued that sustained Cl 2 secretion requires activation of basolateral ( Received in original form July 10, 2000 )