Ein Flip-Flop-Modell des Chlorid-Kanal-Komplexes erklärt die Fehlregulation des Chloridflusses am Plasmalemm von Zellen bei der cystischen Fibrose

Abstract

The basic defect in cystic fibrosis is the chloride impermeability of the plasmalemma in different cells. A candidate for the chloride channel, thought to be affected in the syndrome, is "Porin 31HL" recently described by us. The molecule is i) expressed in the plasmalemma of different cells, it has ii) a molecular mass of 31,000 Daltons, it shows iii) high conductance in artificial membranes and it can be iv) modified by 4,4'-Diisothiocyanatostilbene-2,2'-disulfonate. A porin in the outer membrane of cells should furthermore v) be regulated by modulators. All these characters of "Porin 31HL" correspond to those given in literature for chloride channels. The regulation of the channels can be explained by a two component flip flop model.

Channel Active Mammalian Porin, Purified from Crude Membrane Fractions of Human B Lymphocytes and Bovine Skeletal Muscle, Reversibly Binds Adenosine Triphosphate (ATP)

“…These observations on ATP or stilbene-disulfonate binding by mammalian porin, respectively, in combination with data from our and other laboratories on the expression of eukaryotic porin channels in the plasmalemma of different cells König et a/., 1991;Babel etal., 1991;Cole ef a/., 1992;Puchelle et a/., 1993;Janisch ef a/., 1993;Dermietzel ef a/., 1994) support our proposal that eukaryotic porin might be part of a chloride channel complex which in patch clamp experiments may figure as the outwardly rectifying depolarization induced chloride (ORDIC) channel in different cells (Thinnes ef a/., 1990;1993;1994a;1994b;Thinnes 1992).…”

Studies on Human Porin. VI. Production and Characterization of Eight Monoclonal Mouse Antibodies against the Human VDAC “Porin 31HL” and Their Application for Histotopological Studies in Human Skeletal Muscle

“…Second, VDAC is able to change from anion-to cation-selectivity in correlation with its state of opening [28] .Third, purified VDAC in artificial membranes never close totally, even when membrane potentials are applied that are higher than those physiological for mammalian cells. These facts suggest that biochemical regulation of porin channels takes place when they are incorporated into the plasmalemma of cells [29 l "Porin 31HL" and the chloride channel affected in cystic fibrosis share several characterst 25 ' 29^ On this basis, we have formulated^2 9 ' 30 ! and since refinedâ two-component flip-flop model of a postulated VDAC-containing channel complex misregulated in cystic fibrosis.…”