Intracellular Chloride Channels: Determinants of Function in the Endosomal Pathway

Abstract

Endosomes, and related subcellular compartments, contain various Cl − channels in the ClC family. In this review, we describe the known roles of intracellular Cl − channels and also explore some of the functional implications of transmembrane Cl − flux in these organelles. Cl − influx acts to control intralumenal pH, both by shunting the effects of the proton pump on membrane potential and, possibly, through direct effects of Cl − on the proton pump. Changes in intralumenal pH likely help regulate membrane trafficking. We propose that changes in intralumenal Cl − concentration ([Cl − ]) could theoretically play a direct role in regulating membrane trafficking and organellar function through effects on chloride-sensitive proteins in the vesicular membrane, which could transduce information about intralumenal [Cl − ] to the outside of the vesicle and thereby recruit various signaling molecules. We present a model in which regulation of cytosolic [Cl − ] and vesicular Cl − conductance could help control the amount or type of neurotransmitter stored in a particular population of synaptic vesicles.