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Cation-Chloride Cotransporters in Neuronal Communication

E. Delpire

E. Delpire is Associate Professor in the Departments of Anesthesiology and Molecular Physiology and Biophysics and the Center for Molecular Neurosciences, Vanderbilt University Medical Center, T4202, Medical Center North, Nashville, TN 37232-2520.

	Abstract

 
Two isoforms of the cation-Cl^– cotransporter family are expressed in neurons and modulate neurotransmission. NKCC1, a Na⁺-K⁺-2Cl^– cotransporter, by raising internal Cl^–, is responsible for excitatory GABAergic activity in immature brain and in adult sensory neurons. KCC2, a neuronal-specific isoform of the K⁺-Cl^– cotransporter, by lowering internal Cl^–, is critical for inhibitory GABA responses in mature central nervous system neurons.

	Introduction

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

 
There was a time when the entire focus of neurotransmission research was centered on voltage- and ligand-gated ion channels. It is now clear that many other transport mechanisms play key roles in neuronal communication. Some of these mechanisms participate in the transport of neurotransmitters (today, the antidepressant drug Prozac is well known, and the importance of neurotransmitter reuptake mechanisms at the synapse is well recognized). The role of transport proteins that participate in ion homeostasis, however, has not yet been fully examined. The present review addresses the role of a family of inorganic ion transporters in neurotransmission: the electroneutral cation-Cl^– cotransporters.

	Brain cation-Cl– cotransporters

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

 
To date, seven electroneutral cation-Cl^– cotransporters have been described in mammals: a thiazide-sensitive Na⁺-Cl^– cotransporter (NCC), two loop diuretic-sensitive Na⁺-K⁺-2Cl^– cotransporters (NKCC1 and 2), and four K⁺-Cl^– cotransporters (KCC1–4). NCC and NKCC2 are renal-specific cotransporters. The remaining five cotransporters are more widely expressed and are found in the central nervous system. The precise cellular localizations of KCC1, KCC3, and KCC4 have not yet been reported in the brain. NKCC1 has been localized to choroid plexus, oligodendrocytes, and neurons (9), whereas KCC2 expression has been shown to be restricted to neurons (4, 8). These two cation-Cl^– cotransporters, functioning in opposite directions (Fig. 1), affect GABAergic and glycinergic neurotransmission through regulation of intracellular Cl^– levels.

View larger version (17K): [in this window] [in a new window]   FIGURE 1. Two secondary active cation-Cl– cotransporters expressed in -aminobutyric acid (GABA) and glycine-responsive neurons. NKCC1, Na+-K+-2Cl– cotransporter 1; KCC2, K+-Cl– cotransporter 2; [Cl]i, intracellular Cl– concentration.

	Development of GABAergic, glycinergic, and glutaminergic neurotransmission

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

It has been proposed that GABA-induced depolarizing responses are important signals for growth of neurites, synaptogenesis, and neuronal plasticity (6). This view is, however, not fully supported by conclusions drawn from mice lacking both isoforms of GAD (GAD65 and GAD67) and completely devoid of GABA. Although these mice die shortly after birth because of a cleft palate and inability to suckle, their brains have normal histology and cytoarchitecture at birth. The brains of these double knockout animals seem to refute the trophic role of GABA during neurogenesis. There remains the possibility, however, that in the absence of GABA, another neurotransmitter compensates for and fulfills its trophic function. Also, the trophic role of GABA might be more significant during postnatal development, when a great number of neuronal connections are being made. Finally, the discrepancy between studies showing the importance of GABA in rat neurogenesis and the normal brain histology observed in double GAD knockout mice might merely reflect differences between species.

For mature neurons that use glycine as an inhibitory neurotransmitter, a similar developmental pattern has been described. Early in development, glycine generates depolarizing (excitatory) responses, but later it produces hyperpolarizing (inhibitory) responses. The change of GABA and glycine responses from depolarizing to hyperpolarizing most likely reflects a change in the driving force for Cl^– and a shift in GABA/glycine reversal potential during development.

Two recent studies have examined the intracellular Cl^– concentrations in neurons during development by using the gramicidin-perforated patch technique (2, 7). Both studies have reported a decrease in neuronal Cl^– concentration during postnatal development: the first in GABAergic neurons from the neocortex (Fig. 2A), the second in glycinergic neurons from the auditory brain stem (Fig. 2B).

View larger version (12K): [in this window] [in a new window]   FIGURE 2. Decrease in [Cl]i in developing neurons. A: [Cl]i in cortical neurons was estimated from GABA reversal potential measured with the gramicidin-perforated patch method in rat neocortical slices. Cortical neurons originate and migrate from the ventricular zone. [Cl]i in immature neurons of the ventricular zone is high and decreases on migration and differentiation. Redrawn with permission from Owens and co-workers (7). B: glycine/Cl– reversal potentials (Eglycine) in developing lateral superior olive neurons were measured in auditory brain stem slices with the gramicidin-perforated patch technique. [Cl]i was calculated using the Nernst equation and an external [Cl] of 133.5 mM. E and P, embryonic and postnatal days, respectively. Modified with permission from Ehrlich et al. (2).

	Developmental regulation of NKCC1 and KCC2

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

In contrast to NKCC1, KCC2 expression is low at birth and increases during postnatal development (1, 4). Both mRNA levels and protein levels increase significantly during the first few weeks of postnatal life. The cotransporter is expressed in both cell body and processes, although the KCC2 signal seems more intense at the nerve termini (4, 15).

As indicated in Fig. 3, upregulation of KCC2 and downregulation of NKCC1 are consistent with the significant decrease in intracellular Cl^– observed during postnatal development. This change in the Cl^– driving force is responsible for the shift in direction and nature of GABA and glycine currents that occur during the same period.

View larger version (18K): [in this window] [in a new window]   FIGURE 3. Developmental regulation of NKCC1 and KCC2 expression coincides with changes of GABA-induced Cl– currents from depolarizing (excitatory) to hyperpolarizing (inhibitory). During late embryonic and early postnatal life, immature neurons express the Na+-K+-2Cl– cotransporter. Presence of Na+-K+-2Cl– cotransporter correlates with high [Cl]i in these neurons. On maturation, there is a decrease in Na+-K+-2Cl– cotransporter expression and an increase in expression of the K+-Cl– cotransporter KCC2. These developmental changes coincide with a decrease in [Cl]i. Timing is different in different parts of the brain. Adapted with permission from Lu et al. (4).

	NKCC1 accumulates Cl– in sensory neurons

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

 
Pharmacological evidence now exists to support the role of NKCC1 in accumulating Cl^– in neurons. In contrast to mature central nervous system neurons, peripheral sensory neurons, such as dorsal root ganglion neurons, still exhibit GABA depolarizing currents in the adult. These depolarizing currents are triggered by presynaptic inhibitory axons that establish contact with primary afferent terminals. In this configuration, GABA mediates depolarization of primary afferent terminals, resulting in the blocking of action potential invasion. Thus GABA depolarization initiates presynaptic inhibition, a mechanism that filters the activity of second-order sensory neurons. Using microelectrodes or the gramicidin-perforated patch method, several investigators have demonstrated that amphibian sensory neurons accumulate Cl^– well above electrochemical potential equilibrium. The uphill transport of Cl^– is mediated by a Na⁺-K⁺-2Cl^– cotransporter. Evidence supporting this role of the cotransporter are the Na⁺ and K⁺ sensitivity of Cl^– accumulation and the collapse of the Cl^– gradient with exposure to low concentrations of bumetanide, an inhibitor of the Na⁺-K⁺-2Cl^– cotransporter. Consistent with these functional data is the confirmation of high levels of NKCC1 expression in rat dorsal root ganglion neurons (9).

	Can KCC2 participate in both hyperpolarizing and depolarizing GABA responses?

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

 
As previously mentioned, KCC2 is expressed in the cell body and processes of mature central nervous system neurons (4, 15). Because of the large outward K⁺ gradient, the K⁺-Cl^– cotransporter is capable of driving Cl^– against its own electrochemical gradient and setting internal Cl^– levels to values below electrochemical potential equilibrium. Using antisense oligonucleotides to KCC2, Rivera and co-workers (11) decreased the level of KCC2 expression in postnatal day 11–13 hippocampal slices and demonstrated a positive shift in GABA/Cl^– reversal potential, supporting the view that KCC2 extrudes Cl^– in native pyramidal neurons. Thus KCC2 constitutes the long-sought "Cl^– pumping mechanism" accounting for hyperpolarizing Cl^– influx after brief activation of GABA_A receptors in mature neurons (5, 13).

An interesting feature of GABA neurotransmission, evidenced during high-frequency stimulation, is the reappearance of GABA_A-mediated depolarizing currents. This phenomenon, which occurs at the dendrites but not at cell bodies, is not yet fully understood. It is generally believed that the depolarizing current is mediated by the outward movement of HCO₃^– ions through the GABA_A receptor/Cl^– channel (12). Permeability of the GABA_A receptor to HCO₃^– is ~1/5 of the permeability to Cl^–. The participation of HCO₃^– in GABA currents is difficult to estimate in the presence of a strong driving force for Cl^–. It has been hypothesized, however, that under prolonged stimulation, the Cl^– gradient collapses and the HCO₃^– gradient remains intact. In the absence of a Cl^– gradient, GABA triggers efflux of HCO₃^– ions and membrane depolarization.

What is the basis for the dissipation of the Cl^– gradient? Stimulation of the GABA_A receptor induces entry of Cl^– into the cell. Under normal conditions, this Cl^– could be extruded through a K⁺-Cl^– cotransporter. With high-frequency stimulation, however, the K⁺-Cl^– cotransporter could be rate limiting and Cl^– could accumulate in the neuron and dissipate the driving force. In addition, it has been proposed that repeated stimulation could raise the extracellular K⁺ concentration enough to reverse the driving force for K⁺-Cl^– cotransport.

	A role for the cotransporters in epilepsy?

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

 
Epilepsy is a very common disorder of the central nervous system that manifests itself as abnormal electric discharges in the brain resulting in time-limited alteration in behavior, motor activity, autonomic function, and/or consciousness. Epileptic seizures are the neurological manifestations of hyperexcitable and hypersynchronized electric activity in the brain. One hypothesis for the hyperexcitability is the possibility of abnormal inhibitory signals in the epileptic brain. On the basis of this premise, various antiepileptic drugs target the GABAergic system, either through enhancement of GABA receptor activity or through inhibition of neurotransmitter reuptake, lengthening the time that the neurotransmitter remains in the synaptic cleft. Recent evidence suggests that counteracting excitatory signals must require a subtle and localized regulation by GABA. Indeed, mice that lack GAD65, one of the GAD isoforms, but that seem to maintain normal levels of GABA in their brains have increased susceptibility to epileptic seizures. Furthermore, although both GAD isoforms have been observed in the same GABAergic neurons, some immunohistochemistry and subcellular fractionation studies localize GAD65 preferentially in the nerve terminals.

Using a hippocampal slice preparation, Hochman and co-workers (3) demonstrated that epileptiform discharges induced by tetanic stimulation of Schaffer collaterals, exposure to 4-aminopyridine (a K⁺ channel blocker) or bicuculine (a GABA_A antagonist), or removal of Mg²⁺ were all inhibited by incubation with millimolar concentrations of furosemide (3). Although at these concentrations the inhibition could be explained by a direct effect of the drug on the GABA_A receptor, the furosemide effect might also indicate the participation of a loop diuretic-sensitive cation-Cl^– cotransporter such as KCC2, which is inhibited by loop diuretics like furosemide. Inhibition of KCC2 would likely result in increased intracellular Cl^– concentration, leading to reduced hyperpolarizing inhibitory GABA response and thus hyperexcitability.

	Additional aspects

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

 
Because of their tight relationship to GABAergic neurotransmission, the cotransporters have the capacity to influence many other physiological and pathophysiological processes. First, the cotransporters might be involved in regulating the cyclic firing activity of suprachiasmatic neurons involved in circadian rhythmicity (14). Neurons in this hypothalamic nucleus exhibit GABA depolarizing currents during the day but GABA hyperpolarizing responses at night. Second, the cotransporters might be involved in synchronized thalamocortical activity that occurs during slow wave sleep or anesthesia. Third, the cotransporters might also be involved with the basic mechanisms of alcohol and anesthetic agents through their relationship with the GABA_A receptor. Finally, evidence exists that suggests that neuronal trauma initiates a reversal of GABA currents from hyperpolarizing to depolarizing. These depolarizing GABA currents result in an increase in intracellular Ca²⁺, reminiscent of GABA function in immature neurons.

	Conclusion

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

 
Proper electric activity in the brain results from a delicate balance between excitatory and inhibitory inputs at the synapses. Inhibitory neurotransmission involves the activity of ligand-gated Cl^– channels. Now and then, these channels elicit excitatory responses that depend on the level of intracellular Cl^–. Mechanisms involved in Cl^– homeostasis therefore play a significant role in neurotransmission. Without excluding the importance of other Cl^– transport pathways (the Cl^–/HCO₃^– exchanger and some Cl^– channels such as ClC2), we have discussed in this brief review the evidence implicating NKCC1 and KCC2 in neurotransmission. As the field moves toward new molecular approaches that involve gene knockouts and overexpression, the function of the cation-Cl^– cotransporters in neurotransmission will be further defined.

	NOTE ADDED IN PROOF

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

 
We have recently shown that the Na⁺-K⁺-2Cl^– cotransporter NKCC1 accumulates Cl^– in mouse DRG neurons, a mechanism underlying GABA depolarizing responses in these cells. In mice lacking the cotransporter, DRG neurons fail to accumulate Cl^– and demonstrate abnormal GABA responses. These data, which suggest an absence of depolarization of primary afferent nerve terminals in vivo, are consistent with a sensory perception (nociception) phenotype demonstrated in the NKCC1 knockout mouse (J Neurosci 20: 7531–7538, 2000).

	References

Top Introduction Brain cation-Cl- cotransporters Development of GABAergic,... Developmental regulation of... NKCC1 accumulates Cl- in... Can KCC2 participate in... A role for the... Additional aspects Conclusion NOTE ADDED IN PROOF References

 

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