Biomedical Engineering Reference
In-Depth Information
control human ostereoclasts [
50
]. Loss of ClC-7 leads to lysosomal storage and
neurodegeneration [
51
].
2.2 Cystic Fibrosis Transmembrane Conductance Regulator
CFTR is the first anion channel to be identified by positional cloning. It is a cyclic-
AMP activated plasma membrane chloride channel that has also been assumed to
function as a chloride channel in intracellular organelles, where it could contribute
to support acidification along the exocytic and endocytic pathways [
52
-
54
]. How-
ever, it has been observed that while CFTR may function as a Cl
channel in some
intracellular membranes, the organellar acidification is not dependent on CFTR and
that organellar pH is not abnormal in cystic fibrosis [
44
].
Mutations in CFTR leads to disease cystic fibrosis. However, what are the other
functions of CFTR in intracellular membranes and whether alterations in these
functions contribute to the defects in cystic fibrosis are not well understood. Several
experiments were done to establish ion channel function of CFTR [
55
-
57
]. CFTR is
now known to be a voltage-independent anion channel, which requires the presence
of hydrolyzable nucleoside triphosphates for its efficient activity [
9
].
A spliced form of CFTR is found in cardiac muscle [
58
,
59
]. In fact, the protein
kinase A-regulated cardiac Cl
channel has been found to resemble CFTR [
58
] and
alternative splicing of CFTR Cl
channel in heart has been studied [
59
].
CFTR has been found to act as a regulator of other ion channels, for example,
Na
+
[
60
] and Cl
[
61
,
62
]. The epithelial Na
+
conductance (ENaC) is coexpressed
with CFTR in the apical membrane of most epithelia [
63
], and CFTR and outward
rectifying chloride channels (ORCCs) have been observed to be distinct proteins
with a regulatory relationship [
62
]. Egan et al. [
61
] found that the defective
regulation of ORCCs by protein kinase A could be corrected by insertion of CFTR.
As far as the structure of CFTR is concerned, it has been found that it has 12
transmembrane domains (TMs), two nucleotide binding folds (NBFs), and a regu-
latory R domain (Fig.
2
)[
9
]. It is the only member of the large gene family of ABC
transporters that is known to function as an ion channel. Its opening is controlled by
interacellular ATP and through phosphorylation by cAMP- and cGMP-dependent
kinases. The two NBFs of CFTR differ in their functional characteristics. While
NBF1 is required for channel opening and determines the closed time of the
channel, NBF2 regulates the channel's opening time, but is not required for channel
gating [
9
].
2.3 Ca
2+
-Activated Chloride Channels (CaCC Channels)
CaCC channels are thought to regulate the tonus of smooth muscle and to modulate
excitability by generating after potentials in neurons and muscle cells. In fact, they
