Biomedical Engineering Reference
In-Depth Information
This phenomenon, however, provides the structural basis for the “fast” Cl
-dependent
gating of CLC pores [
29
,
30
]. It is possible that Cl
opens the gate by dislodging the
side chain. The glutamate is conserved in nearly all CLC proteins, with the notable
exception of ClC-K channels, where it is replaced by valine or leucine. Although
several studies support such a role of glutamate in gating, it cannot be generalized.
2.1.3 Specification of CLC Family Members
The CLC family consists of nine separate genes, ClC-1,-2,
, -7, ClC-Ka and
ClC-Kb. Based on the homology and function, they are grouped into three clusters.
The first cluster consists of ClC-1, ClC-2, ClC-Ka and ClC-Kb, the second one
consists of ClC-3, ClC-4 and ClC-5, and the third one consists of only ClC-6
and ClC-7. While the members of the first cluster exert their function in the plasma
membrane, those of second and third function primarily in intracellular mem-
branes. A brief description of tissue distribution, presumed functions and the
human diseases associated with each member is given below.
ClC-1: A muscle-specific Cl
channel, found in skeletal muscle, stabilizes the
membrane voltage, and its mutational inactivation leads to myotonia in humans and
mice [
36
,
37
].
ClC-2: A broadly expressed channel activated by hyperpolarization, cell swelling,
and acidic pH. Its role is not very clear but a role of it in transepithelial transport is
suggested from the testicular and retinal degeneration in mice from its disruption [
38
].
ClC-Ka/Kb: These are two renal Cl
channels that function ( in a heteromeric
complex with barttin, a
...
-subunit of Cl
channel [
39
]) in transepithelial transport
in the kidney and the ear. The mutations in them or in their
b
-subunit barttin cause
Bartter Syndrome associated with kidney failure and deafness [
40
,
41
].
ClC-3: It is expressed in endosomes in many cell types and in synaptic vesicles.
Mutations in ClC-3 in mice result in neurogeneration [
42
].
ClC-4: It is a poorly characterized vesicular channel, not much is known about it.
ClC-5: It is expressed primarily in the renal proximal tubule where it co-
localizes with markers of early apical endosomes [
43
,
44
].
Mutations in ClC-5 lead to Dent's disease, a renal defect associated with low-
molecular-weight proteinuria, hyperphosphaturia, hypercalicuria, and aminoacidiuria
[
45
]. Probably similar to ClC-3, ClC-5 provides a shunt for the H
+
-ATPase that
is necessary for the efficient acidification of endosomes.
ClC-6: It is expressed in late endosomes in the nervous system and its disruption
results in neurogeneration with pathological features of lysosomal storage disease
[
42
,
44
].
ClC-7: It is a lysosomal Cl
channel, also expressed in late endosomes [
44
].
It accounts for the major Cl
permeability of lysosomes [
46
]. Mutations in ClC-7
leads to osteoporosis in mice and humans [
47
,
48
], and osteoclasts derived from
patients harboring ClC-7 mutations show defective bone resorption [
49
,
50
]. ClC-7
leads to acidification of lysosome, as a result an acid flux was characterized in
b
