Limits...
Development and regulation of chloride homeostasis in the central nervous system.

Watanabe M, Fukuda A - Front Cell Neurosci (2015)

Bottom Line: Generally, developmental shifts (decreases) in [Cl(-)]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex.KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1).Therefore, regional developmental regulation of these regulators and modulators of Cl(-) transporters may also play a pivotal role in the development of Cl(-) homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine Hamamatsu, Japan.

ABSTRACT
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mature central nervous system (CNS). The developmental switch of GABAergic transmission from excitation to inhibition is induced by changes in Cl(-) gradients, which are generated by cation-Cl(-) co-transporters. An accumulation of Cl(-) by the Na(+)-K(+)-2Cl(-) co-transporter (NKCC1) increases the intracellular Cl(-) concentration ([Cl(-)]i) such that GABA depolarizes neuronal precursors and immature neurons. The subsequent ontogenetic switch, i.e., upregulation of the Cl(-)-extruder KCC2, which is a neuron-specific K(+)-Cl(-) co-transporter, with or without downregulation of NKCC1, results in low [Cl(-)]i levels and the hyperpolarizing action of GABA in mature neurons. Development of Cl(-) homeostasis depends on developmental changes in NKCC1 and KCC2 expression. Generally, developmental shifts (decreases) in [Cl(-)]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex. There are several regulators of KCC2 and/or NKCC1 expression, including brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF), and cystic fibrosis transmembrane conductance regulator (CFTR). Therefore, regionally different expression of these regulators may also contribute to the regional developmental shifts of Cl(-) homeostasis. KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1). In addition, activation of these kinases is modulated by humoral factors such as estrogen and taurine. Because these transporters use the electrochemical driving force of Na(+) and K(+) ions, topographical interaction with the Na(+)-K(+) ATPase and its modulators such as creatine kinase (CK) should modulate functions of Cl(-) transporters. Therefore, regional developmental regulation of these regulators and modulators of Cl(-) transporters may also play a pivotal role in the development of Cl(-) homeostasis.

No MeSH data available.


Related in: MedlinePlus

Developmental changes in factors regulating Cl− transporter transcription and function.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585146&req=5

Figure 3: Developmental changes in factors regulating Cl− transporter transcription and function.

Mentions: The developmental increase of factors that regulate NKCC1 and KCC2 gene expression is correlated with the time course of the developmental switch of the GABAAR response. The developmental increase in NKCC1 and KCC2 protein expression is modulated by neurotrophic factors (Figure 3). Brain-derived neurotrophic factor (BDNF) exerts a facilitatory effect on the expression of KCC2 mRNA and protein during development. Increased expression of KCC2 mRNA in the hippocampus of BDNF-overexpressing transgenic mice at E18 reduced [Cl–]i and then decreased [Ca2+]i transients evoked by GABAA receptor activation (Aguado et al., 2003). Conversely, the expression of KCC2 mRNA is decreased in the hippocampus of tyrosine receptor kinase B (TrkB) receptor mice at P10 (Carmona et al., 2006). This facilitatory effect of BDNF on KCC2 protein expression occurs via extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent upregulation of the transcription factor early growth response 4 (Egr4) and via Egr4-dependent activation of the KCC2b promoter (Ludwig et al., 2011). The trophic factor neurturin (NRTN) could also trigger Egr4 mRNA expression and upregulate KCC2 protein in an ERK1/2-dependent manner in developing neurons (Rivera et al., 2011). NRTN belongs to the GDNF family of neurotrophic factors and binds to the GPI-anchored receptor GDNF family receptor 2 (GRFα2).


Development and regulation of chloride homeostasis in the central nervous system.

Watanabe M, Fukuda A - Front Cell Neurosci (2015)

Developmental changes in factors regulating Cl− transporter transcription and function.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585146&req=5

Figure 3: Developmental changes in factors regulating Cl− transporter transcription and function.
Mentions: The developmental increase of factors that regulate NKCC1 and KCC2 gene expression is correlated with the time course of the developmental switch of the GABAAR response. The developmental increase in NKCC1 and KCC2 protein expression is modulated by neurotrophic factors (Figure 3). Brain-derived neurotrophic factor (BDNF) exerts a facilitatory effect on the expression of KCC2 mRNA and protein during development. Increased expression of KCC2 mRNA in the hippocampus of BDNF-overexpressing transgenic mice at E18 reduced [Cl–]i and then decreased [Ca2+]i transients evoked by GABAA receptor activation (Aguado et al., 2003). Conversely, the expression of KCC2 mRNA is decreased in the hippocampus of tyrosine receptor kinase B (TrkB) receptor mice at P10 (Carmona et al., 2006). This facilitatory effect of BDNF on KCC2 protein expression occurs via extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent upregulation of the transcription factor early growth response 4 (Egr4) and via Egr4-dependent activation of the KCC2b promoter (Ludwig et al., 2011). The trophic factor neurturin (NRTN) could also trigger Egr4 mRNA expression and upregulate KCC2 protein in an ERK1/2-dependent manner in developing neurons (Rivera et al., 2011). NRTN belongs to the GDNF family of neurotrophic factors and binds to the GPI-anchored receptor GDNF family receptor 2 (GRFα2).

Bottom Line: Generally, developmental shifts (decreases) in [Cl(-)]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex.KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1).Therefore, regional developmental regulation of these regulators and modulators of Cl(-) transporters may also play a pivotal role in the development of Cl(-) homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine Hamamatsu, Japan.

ABSTRACT
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mature central nervous system (CNS). The developmental switch of GABAergic transmission from excitation to inhibition is induced by changes in Cl(-) gradients, which are generated by cation-Cl(-) co-transporters. An accumulation of Cl(-) by the Na(+)-K(+)-2Cl(-) co-transporter (NKCC1) increases the intracellular Cl(-) concentration ([Cl(-)]i) such that GABA depolarizes neuronal precursors and immature neurons. The subsequent ontogenetic switch, i.e., upregulation of the Cl(-)-extruder KCC2, which is a neuron-specific K(+)-Cl(-) co-transporter, with or without downregulation of NKCC1, results in low [Cl(-)]i levels and the hyperpolarizing action of GABA in mature neurons. Development of Cl(-) homeostasis depends on developmental changes in NKCC1 and KCC2 expression. Generally, developmental shifts (decreases) in [Cl(-)]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex. There are several regulators of KCC2 and/or NKCC1 expression, including brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF), and cystic fibrosis transmembrane conductance regulator (CFTR). Therefore, regionally different expression of these regulators may also contribute to the regional developmental shifts of Cl(-) homeostasis. KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1). In addition, activation of these kinases is modulated by humoral factors such as estrogen and taurine. Because these transporters use the electrochemical driving force of Na(+) and K(+) ions, topographical interaction with the Na(+)-K(+) ATPase and its modulators such as creatine kinase (CK) should modulate functions of Cl(-) transporters. Therefore, regional developmental regulation of these regulators and modulators of Cl(-) transporters may also play a pivotal role in the development of Cl(-) homeostasis.

No MeSH data available.


Related in: MedlinePlus