Ionic channels in epithelial cell membranes

Abstract

This review focused on results obtained with methods that allow studies of ionic channels in situ, namely, patch clamping and current-noise analysis. We reported findings for ionic channels in apical and basolateral plasma membranes of various tight and leaky epithelia from a wide range of animal species and tissues. As for ionic channel "species," we restricted ourselves to the discussion of cation-specific (Na+ or K+), hybrid (Na+ and K+), and Cl- channels. For the K+-specific channels it can be said that their properties in conduction (multisite, single file), selectivity (only "K+-like" cations), and blocking behavior (Ba2+, Cs+, TEA) much resemble those observed for K+ channels in excitable membranes. This seems to include also the Ca2+-activated "maxi" K+ channel. Thus, K+ channels in excitable membranes and K+ channels in epithelia appear to be very closely related in their basic structural principles. This is, however, not at all unexpected, because K+ channels provide the dominant permeability characteristics of nearly all plasma membranes from symmetrical and epithelial cells. An exception is, of course, apical membranes of tight epithelia whose duty is Na+ absorption against large electrochemical gradients in a usually anisosmotic environment. Here, Na+ channels dominate, although a minor fraction of membrane permeability comes from K+ channels, as in frog skin, colon, or distal nephron. Epithelial Na+ channels are different from excitable Na+ channels in that they 1) are far more selective and 2) seem to be chemically rather than electrically gated. Furthermore, their specific blockers belong to very different chemical families, although a guanidinium/amidinium moiety is a common feature (TTX vs. amiloride). [For a more detailed summary of Na+ channel properties see sect. IV H.] Most interesting is the occurrence of relatively nonselective cationic (hybrid) channels in apical membranes of tight epithelia, like larval or adult frog skin. Here, not only the weak selectivity is astonishing but also the fact that these channels react with so-called K+-channel-specific (Ba2+, TEA) as well as with Na+-channel-specific (amiloride, BIG) compounds. Moreover, this cross-reactivity does not seem to be inhibitory but, on the contrary, stimulating. Clearly these channels may become a fascinating object with which to assess whether Na+ and K+ channels are not only structurally but also genetically related and whether they can somehow be converted into each other.(ABSTRACT TRUNCATED AT 400 WORDS)

Extracellular Zn2+ Activates Epithelial Na+ Channels by Eliminating Na+ Self-inhibition

“…Our previous results and work from other investigators suggest that ENaC gating is regulated in an allosteric manner by extracellular cues (5,9,11). These observations raise the possibility that ENaC is a ligand-gated channel, similar to ATP-sensitive inward rectifier K ϩ channels (K ATP ) (35), cyclic nucleotide-gated channels (36), and glutamate receptor ion channels (37).…”

“…Extracellular cations have been reported to affect ENaC activity in native tissues that may reflect changes in Na ϩ selfinhibition (3,5). We and others previously reported that external Ni 2ϩ blocks whole cell currents of ␣␤␥ ENaCs expressed in oocytes (10,11).…”

“…The stimulatory effect of Zn 2ϩ depends on the extracellular Na ϩ concentration, a key factor in the Na ϩ self-inhibition response. Extracellular divalent cations, including Zn 2ϩ , Cd 2ϩ , Cu 2ϩ , and Ni 2ϩ , have been previously shown to stimulate amiloride-sensitive Na ϩ currents in Na ϩ -transporting epithelial tissues such as frog skin and toad urinary bladder (5,20). Although external Ni 2ϩ is a blocker of mouse and rat ENaCs expressed in Xenopus oocytes (10,11), extracellular Ni 2ϩ was found to stimulate amiloride-sensitive short-circuit current in A6 cells by competitively interfering with Na ϩ selfinhibition (12).…”

“…In addition to the imidazole nitrogen of ␥H239, other moieties such as -SH groups from Cys residues that are abundant within the ECLs of ENaC subunits may participate in forming a high affinity binding site for Zn 2ϩ . Reagents that are capable of reacting with sulfhydryl groups, as well as extracellular cations that are often coordinated by Cys (Cd 2ϩ , Zn 2ϩ , and Cu 2ϩ ), have been shown to stimulate Na ϩ transport across model epithelia, a response that likely reflects a loss of Na ϩ self-inhibition (5). According to this model, Zn 2ϩ binding would prevent or reverse Na ϩ binding and thus eliminate Na ϩ -induced conformational changes that ultimately lead to a P o reduction.…”

“…Na ϩ exhibits two types of inhibitory effects on ENaC activity: self-inhibition and feedback inhibition that are due to increases in either extracellular or intracellular Na ϩ concentration, respectively. These regulatory phenomena have been proposed to provide a mechanism to prevent sudden or excessive increases in intracellular Na ϩ concentration (5,6).…”