Biomedical Engineering Reference
In-Depth Information
domains facilitate the insertion and proper refolding of CLICs to form functional
channels.
2.5.3 Functions of CLICs
There are several hypotheses regarding the functions of CLICs. According to one
hypothesis, the CLICs can function as ion channels, while another hypothesis is that
they possess other functions in the cell, which do not appear to be related to channel
activity. CLICs are also supposed to be multifunctional proteins that can transition
between the integral membrane forms, which support ion channel activity, and the
soluble globular forms, that may support regulation of various cell processes, such
as structure of the cytoskeleton or modulation of gene expression. Control of their
distribution between soluble globular and integral membrane forms is central to the
understanding of their mode of function [
44
].
CLICs behave as atypical ion channels and function as intracellular ion channels
with limited physiological roles. They are implicated in several important
functions, such as membrane trafficking, cytoskeletal function, apoptosis, cell
cycle control, mitosis, and differentiation [
11
]. However, there is limited evidence
to believe that they function as Cl
channels in intracellular membranes. There
are only three systems for which some reports are available for their function
as Cl
channels: CLIC1 in nuclear membrane, CLIC4 in vesicles along the intra-
cellular tubulogenic pathway, and CLIC5B in osteoclast ruffled membrane.
2.6 Bestrophins
Bestrophins are a group of four proteins, which have been found to support Cl
channel activity when overexpressed in cell expression system [
116
,
117
]. Some
studies on mutagenesis, in which mutation of the bestrophin causes discrete
changes in the associated channel activity, led to assume that they themselves
function as channels [
44
]. The first member of the bestrophin family, bestrophin
1, is assumed to primarily reside in epithelium reticulum (ER) and not in the plasma
membrane [
118
]. An observation that bestrophin 1 modulates both Ca
2+
release and
uptake from interacellular stores, presumably ER, leads to assume that bestrophin
functions as an ER chloride channel, which could provide counter ion movement
during cycles of Ca
2+
release and uptake [
117
]. However, it is only an indirect
evidence to say that bestrophin functions as a channel in the ER; it only suggests
that bestrophin facilitates only Ca
2+
movement. The identification of bestrophin 1
as the site of mutation in the Best's disease, a form of early onset macular
degeneration [
116
,
117
], simply supports a Ca
2+
-activated chloride current in the
basal membrane of the retinal pigment epithelium. It hardly provides any direct
evidence that bestrophin 1 itself functions as chloride ion channel [
119
].
