Intracellular chloride channels: determinants of function in the endosomal pathway

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.