TMEM16 Ca2+ Activated Cl– Channels and CLC Chloride Channels and Transporters

Abstract After the identification of TMEM16 proteins as the molecular counterparts of Ca2+-activated Cl– channels, their roles in shaping excitability in several parts of the central and peripheral nervous system are emerging. Their contribution might be excitatory, as in dorsal root ganglion neurons and olfactory sensory neurons, or at the contrary, contributing to hyperpolarization, as in thalamocortical neurons, being strictly related to the equilibrium potential for chloride that can differ among cells or cellular compartments. The ClC-2 channel, together with its auxiliary subunit GlialCAM, is most important in glia, and mutations in the CLCN2 and GLIALCAM genes lead to leukodystrophy. The endo/lysosomal chloride/proton antiporters ClC-3, ClC-4, ClC-6, and ClC-7/Ostm1 are involved in the homeostasis of endosomes and lysosomes, and ClC-3/ClC-4 may be involved in neurotransmitter loading of synaptic vesicles. Mutations in CLCN4 cause intellectual disability, and recessive mutations in CLCN7 or OSTM1 are associated with neurodegeneration.