Abstract
The intraneuronal ionic composition is an important determinant of brain functioning. There is growing evidence that aberrant homeostasis of the intracellular concentration of Cl− ([Cl−]i) evokes, in addition to that of Na+ and Ca2+, robust impairments of neuronal excitability and neurotransmission and thereby neurological conditions. More specifically, understanding the mechanisms underlying regulation of [Cl−]i is crucial for deciphering the variability in GABAergic and glycinergic signaling of neurons, in both health and disease. The homeostatic level of [Cl−]i is determined by various regulatory mechanisms, including those mediated by plasma membrane Cl− channels and transporters. This review focuses on the latest advances in identification, regulation and characterization of Cl− channels and transporters that modulate neuronal excitability and cell volume. By putting special emphasis on neurons of the olivocerebellar system, we establish that Cl− channels and transporters play an indispensable role in determining their [Cl−]i and thereby their function in sensorimotor coordination.
Highlights
Reviewed by: Mauricio Di Fulvio, Wright State University, United States Klaus-Peter Hoffmann, University Hospitals of the Ruhr-University of Bochum, Germany
If ECl becomes more positive compared to the resting membrane potential (RMP), outward Cl− flow through GABAA receptors (GABAARs) leads to excitation of the postsynaptic neuron (Figure 1Bc)
Neurons express a rich set of plasma membrane Cl− channels and transporters, which belong to various protein families and have different modes of activation
Summary
One of the well-known families of HCO−3 transporters is the SLC4 family of Cl−/HCO−3 exchangers, which is widely expressed in the body This family contains 10 members (SLC4A1-5 and A7-11), with some mediating Na+-independent Cl−/HCO−3 exchange (Anion Exchanger 1-3 or AE1-AE3) and some isoforms facilitating Na+-dependent Cl−/HCO−3 exchange (NCBE and NDCBE). In hippocampal pyramidal cells elevated pH levels activate bAE3, which leads to HCO−3 extrusion, a function essential for recovery of intracellular alkalosis (Hentschke et al, 2006). SLC4A10 (NCBE) NCBE functions as a Na+-dependent Cl−/HCO−3 exchanger It is expressed in the olfactory bulb, cerebral cortex, brain stem, spinal cord, and cerebellum (Jacobs et al, 2008). Similar to SLC4A8 (NDCBE), NCBE may mediate the inward transport of Na+ and HCO−3 in exchange for intracellular Cl− (Figure 2).
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