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News Physiol Sci 16: 167-170, 2001;
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News in Physiological Sciences, Vol. 16, No. 4, 167-170, August 2001
© 2001 Int. Union Physiol. Sci./Am. Physiol. Soc.

CFTR: Interacting With Everything?

Karl Kunzelmann

Department of Physiology and Pharmacology, University of Queensland, St. Lucia, Queensland 4072, Australia

   Abstract
 
More than 1,300 different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) are the cause for cystic fibrosis. CFTR is in charge of proper secretion and absorption of electrolytes, and thus the disease is characterized by defective epithelial Cl– secretion and enhanced Na+ absorption. Recent studies show that CFTR interacts with other proteins via PDZ domains.


   Introduction
Top
 Introduction
Defective Cl- secretion and...
 Is there anything that...
 CFTR communicates via PDZ...
 Interaction of CFTR with...
 References
 
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-and protein kinase A (PKA)-regulated Cl– channel and a regulator of other ion channels (3, 10, 12) (Fig. 1Go). In normal, non-cystic fibrosis (CF) epithelial cells and in recombinant cells overexpressing CFTR, large Cl– currents are activated on increase in intracellular cAMP. In patch-clamp single-channel recordings, low-conductance CFTR Cl– currents are observed that cannot be detected in epithelial cells derived from CF patients. CFTR is expressed in luminal membranes of both secretory and absorptive epithelia, and CFTR plays a predominant role in both cAMP- and Ca2+-activated secretion of electrolytes. It forms the luminal exit pathway for Cl–, which has been taken up by the basolateral Na+-K+-2Cl– cotransporter (3). Apart from its secretory function, CFTR also regulates absorption of electrolytes by controlling the activity of the epithelial Na+ channel (ENaC) in absorptive epithelial cells in colon, airways, and sweat ducts (Fig. 1Go). In contrast to colon and airways, in which CFTR has an inhibitory effect on ENaC upon activation by PKA, CFTR is required for activation of ENaC in the sweat ducts (9).



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  		FIGURE 1. Cellular models of electrolyte secretion and electrolyte absorption in the airways and intestinal epithelium. A: in secretory cells, Cl– is taken up from the basolateral (blood) side by the Na+-K+-2Cl– cotransporter. K+ recycles via basolateral K+ channels, and Na+ is pumped out of the cell by the Na+-K+-ATPase. Cl– leaves the cell via luminal (apical) cystic fibrosis transmembrane conductance regulator (CFTR) Cl– channels, and Na+ is secreted via the paracellular shunt. K+ is also secreted to the luminal side via luminal K+ channels. Depending on the tissue, intracellular cAMP is increased and secretion is activated by adenosine or prostaglandin E2 (PGE2). B: in absorptive epithelial cells, Na+ is taken up by luminal epithelial Na+ channels (ENaC). Cl– is transported via the basolateral shunt and probably via CFTR Cl– channels. Na+ is pumped out of the cell by the basolateral Na+-K+-ATPase, whereas Cl– and K+ leave the cell via Cl– and K+ channels, respectively. In these absorptive epithelial cells that coexpress CFTR and ENaC, stimulation of CFTR leads to inhibition of ENaC.

 

   Defective Cl– secretion and enhanced Na+ absorption in CF
Top
 Introduction
 Defective Cl- secretion and...
Is there anything that...
 CFTR communicates via PDZ...
 Interaction of CFTR with...
 References
 
The way that CFTR interacts with ENaC and other ion channels is still unknown and is currently under investigation (5). Because defects in CFTR lead to defective regulation of ENaC, CF is characterized by disturbances in both secretion and absorption of electrolytes. Regarding the life-threatening lung disease in CF, two pathophysiological mechanisms are crucial: 1) the impaired secretion of Cl–, which is located preferentially in the submucosal glands, and 2) the enhanced absorption of Na+ and consecutive hyperabsorption of electrolytes, which takes place in the surface epithelium (Fig. 2Go). In the normal airways, ion transport is switched from net absorption under resting conditions to a net secretion when exposed to secretagogues. However, CF airways are unable to enhance their secretory transport on stimulation. In contrast, the enhanced epithelial Na+ conductance in apical membranes, in parallel with a paracellular permeability for Cl– and the high water permeability that does not allow large transepithelial osmotic gradients, leads to hyperabsorption in CF epithelia (6). Thus the airway surface liquid layer is reduced, submucosal glands are no longer cleared from mucus, and mucociliary clearance is largely impaired in CF airways (Fig. 2Go). CF is caused by a large number of different mutations that affect CFTR function in different ways (17, 20). Counteracting the deleterious effects of these mutations by recovering at least residual CFTR Cl– channel activity is the primary goal of a new pharmacotherapy of the ion transport defect in CF.



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  		FIGURE 2. Model of the airway epithelium consisting of an absorptive surface epithelium and secretory submucosal glands. Secretion of electrolyte by the submucosal glands covers the airways with an airway surface liquid film, which is essential for proper mucociliary clearance. Secretion is also essential to clear the submucosal glands of mucus. Both secretory and absorptive processes are defective in cystic fibrosis (CF), since net absorption of electrolytes is enhanced in the CF surface epithelium and secretion by the submucosal glands is inhibited.

 

   Is there anything that is not affected by CFTR?
Top
 Introduction
 Defective Cl- secretion and...
 Is there anything that...
CFTR communicates via PDZ...
 Interaction of CFTR with...
 References
 
CF is characterized by a multitude of symptoms. This is explained by the fact that all types of epithelial tissues are affected (Table 1Go). Some symptoms and cellular defects are due to defective regulation of a variety of other membrane transport processes and CFTR-independent cellular proteins (5). So far, the best-examined example is the negative impact of CFTR on the epithelial Na+ conductance. Regulation of ENaC by CFTR has been studied in detail in epithelial tissues from intestine and trachea as well as in renal cells. We have demonstrated that the functional first nucleotide binding fold (NBF1) is a requirement for regulation of ENaC by CFTR (11). According to this notion, other CFTR interactions also rely on an intact NBF1 (c.f. Table 1Go). A number of hypotheses have been presented as to how CFTR might control ENaC activity (3). There are clear hints suggesting that the Cl– transport caused by CFTR activity or, eventually, that local changes of the Cl– concentration in close proximity to the plasma membrane are causing inhibition of the Na+ channel. Such a mechanism is reminiscent of the so-called Na+ feedback in Na+-absorbing epithelia, which has been known for a long time and for which the molecular details are currently under investigation (2). Alternatively, it might be the cellular uptake of Na+, which is tightly coupled to that of Cl–, that is causing the inhibition.


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  		TABLE 1. Summary of the interactions of cystic fibrosis transmembrane conductance regulator with other transport proteins
 
Noticeably, the inhibition of ENaC by CFTR is not present in the sweat duct epithelium (9). In contrast to colon and airways, the sweat duct is devoted exclusively to absorption of electrolytes and even requires CFTR for activation of ENaC. Thus both Cl– and Na+ conductances are low in the apical membrane of the CF sweat duct. This essential difference between both types of epithelia may reflect differential expression of accessory proteins necessary for the CFTR/ENaC interaction. The respective proteins eventually interact via PDZ domains.


   CFTR communicates via PDZ domains
Top
 Introduction
 Defective Cl- secretion and...
 Is there anything that...
 CFTR communicates via PDZ...
Interaction of CFTR with...
 References
 
Recently, CF scientists demonstrated great interest in a short stretch of amino acids at the COOH terminal end of CFTR. These four amino acids form a common motif for protein interaction called a PDZ binding domain (18). In this respect, there was controversy over whether CFTR functions as a monomer, thus forming individual Cl– channels, or whether a conductive unit is composed of two or even more CFTR proteins (13).

Data have been acquired over the past few years consistent with the model of CFTR as a monomeric channel. Other observations implicate a possible homomeric CFTR-CFTR interaction and formation of protein dimers. The dimer hypothesis was reinforced recently by cloning of the multivalent CFTR binding protein CAP70, a CFTR-associated protein of 70 kDa that is expressed primarily in kidney and small intestine. CAP70 was also shown to colocalize in cell membranes of cultured airway epithelial cells (19). CAP70 contains four PDZ domains and may use two of these domains, PDZ3 and PDZ4, to link together two CFTR proteins. Interestingly, dimerization of CFTR by CAP70 had no impact on the single channel conductance but increased the open probability of the CFTR Cl– channel and thus potentiated the CFTR Cl– current (Fig. 3Go). Thus the CFTR channel may form transitional dimers of higher Cl– channel activity that represent a novel way of regulating the activity of ATP binding casette transporters. Whether such a regulatory interaction really takes place in the native epithelium remains to be demonstrated.



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  		FIGURE 3. Postulated role of PDZ domain proteins in regulating CFTR activity and participation in CFTR-dependent regulation of ENaC. Hypothetical arrangement of CFTR, ENaC, and accessory PDZ domain proteins is shown. PDZ domain proteins such as CAP70, Na+/H+ exchange regulatory factor (NHERF), ezrin binding protein 50 (EBP50), or Na+/H+ exchange type 3 kinase A regulatory protein (E3KARP) may be involved in regulation of CFTR activity by formation of CFTR-CFTR dimers, cytoskeletal anchoring of CFTR, or protein kinase A (PKA)-dependent phosphorylation of CFTR. Interaction with other membrane proteins such as ENaC could be mediated by nonreceptor kinases binding to these PDZ domain proteins. NBF, nucleotide binding fold; YAP, Yes-associated protein.

 
Future studies will also have to demonstrate how CAP70 competes with other PDZ domain proteins for the binding to the COOH terminus of CFTR. The ezrin binding phosphoprotein 50 (EBP50) was the first protein that was reported to bind to the COOH terminus of CFTR (14). EBP50 is colocalized in apical membranes of airway epithelial cells together with CFTR. Although ultimate experimental proof for in vivo function has not yet been supplied, ezrin might act as an A kinase anchoring protein. Thus a crucial role has been attributed to these PDZ binding domain proteins in translocating PKA to the plasma membrane and in close proximity to CFTR (Fig. 3Go). Such a network of proteins would allow for efficient activation of CFTR by an increase in intracellular cAMP and PKA-dependent phosphorylation (14–16). It will be interesting to see the quantitative impact of these proteins and the PDZ binding domain on PKA-dependent activation of CFTR. At least in Xenopus oocytes, PKA was shown to be able to activate CFTR even in the absence of this PDZ binding domain (4).


   Interaction of CFTR with other ion channels via PDZ domains?
Top
 Introduction
 Defective Cl- secretion and...
 Is there anything that...
 CFTR communicates via PDZ...
 Interaction of CFTR with...
References
 
Other PDZ proteins related to EBP50 have been shown to bind to CFTR such as the Na+/H+ exchange regulatory factor (NHERF) and the Na+/H+ exchanger type 3 kinase A regulatory protein. It has been demonstrated that, apart from their ability to recruit ezrin and probably PKA to the apical membrane, these scaffolding proteins anchor CFTR to the apical membrane via ezrin and interaction with the actin cytoskeleton (8, 16). Interestingly, some receptor proteins, like the ß2-adrenergic receptor or the purinergic P2Y1 receptor, also bind to PDZ domain proteins. Thus these PDZ-carrying proteins represent a family of multifunctional adapter proteins that are potentially involved in many aspects of intracellular signaling (1).

In this regard, PDZ-carrying scaffolding proteins may offer a way to explain how CFTR controls the activity of other ion channels such as ENaC (Fig. 3Go). It has been shown that EBP50 interacts with the Yes-associated protein YAP65 that recruits c-Yes to the apical plasma membrane. The nonreceptor tyrosine kinase c-Yes and other kinases of the Src family are known to regulate ion channel activity (7). Regulation of ENaC (and other ion channels) could occur through phosphorylation by such nonreceptor kinases. However, currently there is no evidence that these regulatory mechanisms are realized in intact cells. Activation of CFTR was only slightly enhanced after coexpression with NHERF and ezrin in Xenopus oocytes (16). Moreover, data from our laboratory demonstrate that membrane targeting and cAMP-dependent activation of CFTR takes place in Xenopus oocytes even in the absence of a functional PDZ binding domain (4). Noticeably, inhibition of ENaC by CFTR occurs even with COOH-terminally truncated CFTR and is not disturbed when mutant NHERF1 or NHERF2 are coexpressed together with CFTR and ENaC in Xenopus oocytes (4).

An attractive model, of course, would be that of clusters of functionally related proteins organized in membrane microdomains. These clusters would contain all elements required for membrane transport and signal transduction and thus regulation and interaction of ion channels and receptors. Differential expression of PDZ domain proteins and preferential binding to certain PDZ motifs may allow for differential regulation in various cell types. For example, this could explain the different kind of interaction between CFTR and ENaC in airways/colon and sweat ducts. Therefore, more work has to be done to sort out the contribution of these PDZ domain proteins to CFTR-dependent regulation, particularly in the native epithelial cell.


   Acknowledgments
 
This work is supported by Deutsche Forschungsgemeinschaft Grant Ku756/4-1, Zentrum klinische Forschung, and Mukoviszidose e.V.


   References
Top
 Introduction
 Defective Cl- secretion and...
 Is there anything that...
 CFTR communicates via PDZ...
 Interaction of CFTR with...
 References
 

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  2. Komwatana P, Dinudom A, Young JA, and Cook DI. Cytosolic Na+ controls an epithelial Na+ channel via Go guanine nucleotide-binding regulatory protein. Proc Natl Acad Sci USA 93: 8107–8111, 1996.[Abstract/Free Full Text]
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