Neuronal Chloride Transporters in Health and Disease

Front Matter
Copyright
Contributors
Preface
Acknowledgments
A historical overview of chloride transporter research
	Introduction
	Early CCC biology research and the emergence of neuronal Cl- transport theory
	The cloning of CCC genes and the elucidation of their expression patterns in the CNS
	Part I: Function of neuronal chloride transporters in regulating neuronal chloride homeostasis and brain development
	Part II: Function of KCC2 in regulating excitatory synapse development
	Part III: The molecular and cellular biology of neuronal chloride transporters
	Part IV: Linking neuronal chloride transporter deficiencies to nervous system diseases
	Part V: Development of therapies targeting neuronal chloride transporters
	Future directions
	References
Methods for investigating the activities of neuronal chloride transporters
	Introduction
	Electroneutrality and general principles of the analysis of ion-transport activity of NKCC1
	Analysis of KCC2 ion-transport activity: Electroneutrality and general principles
	Pioneer works to record NKCC and KCC activities
	K+ surrogate approaches
		86Rb+ influx assay
		Tl+ flux assay
		NH4+ flux assay
	Measurements of resting [Cl-]i
		Gramicidin perforated patch clamp (GPPC) recording
		Recording of single GABAA and NMDA channel in cell attached configuration
		Other approaches to record DFGABA and DFGly
		Quinolinium halid-sensitive indicators
		Genetically encoded Cl--sensitive indicators
	Measurements of Cl- extrusion
	References
The relation between neuronal chloride transporter activities, GABA inhibition, and neuronal activity
	Passive and active Cl- transport across membranes
	Expression of Cl- loaders and Cl- extruders
	Relation between Cl- transporters, [Cl-]i, and GABAergic actions
	When is a depolarization excitatory?
	Input and context specificity of depolarizing GABAergic inputs
	Some examples for excitatory and inhibitory GABAergic actions in the immature CNS
	References
Chloride transporter activities shape early brain circuit development
	Introduction
	Ontogenesis of chloride extrusion in CNS neurons
	Chloride transporter activities shape the cellular actions of GABA and glycine in the developing CNS
		NKCC1 and GABAergic/glycinergic depolarization in immature neurons
		The developmental ECl- shift
		A perinatal ECl- shift in altricial species?
		GABA/glycine actions and steady-state [Cl-]i in developing neurons in vivo
	Chloride transporter activities affect patterned network activity during CNS development
		Patterned network activity in developing neural circuits
		A role for GABAergic depolarization in the generation of early cluster activity
		KCC2 and the developmental emergence of sparse firing
	Chloride transporter activities shape synaptic and neuronal network maturation in the developing CNS
		How chloride transporters may affect neuronal development
		Evidence for a role of chloride co-transporters in CNS development in vivo
	Concluding remarks
	References
Regulation of neuronal cell migration and cortical development by chloride transporter activities
	Roles of chloride transporter activities in the migration of glutamatergic neuronal precursors in the developing neocortex
	Roles of chloride transporter activities in the migration of GABAergic neuronal precursors in the developing neocortex
	Roles of chloride transporters in neuronal maturation in the developing neocortex
	Concluding remarks: Comparison of the roles of Cl- transporters between glutamatergic and GABAergic precursors in the devel ...
	References
KCC2 regulates dendritic spine development
	Introduction
	Development of dendritic spines
	KCC2 expression is enriched in dendritic spines
	KCC2 regulates synaptogenesis through interaction with 4.1N
	KCC2 regulates actin turnover in dendritic spines through interaction with β-PIX
	Global morphogenic role of KCC2
	Reciprocal regulation of KCC2 expression and glutamatergic activity
	Conclusions
	Acknowledgments
	References
Transport-dependent and independent functions of KCC2 at excitatory synapses
	Introduction
	KCC2 expression in the vicinity of excitatory synapses
	KCC2 interacts with synaptic and perisynaptic proteins
	KCC2 activity and the regulation of dendritic spine volume
	KCC2-actin interaction hinders protein diffusion in dendritic spines
	KCC2-dependent control of actin dynamics and long term potentiation at glutamatergic synapses
	Conclusions
	References
KCC2 is a hub protein that balances excitation and inhibition
	Introduction
	Hub proteins
		KCC2 has a dense PPI network
		KCC2 is evolutionarily conserved and essential for survival
		KCC2 interactome is dynamic
	KCC2 is a functional hub protein regulating both inhibition and excitation
		KCC2 and GABAergic synaptic transmission
		KCC2 at excitatory synapses
		KCC2 at the nexus of excitation-inhibition balance
	Conclusion
	References
Current structural view on potassium chloride co-transporters
	Introduction
	Sequence conservation between K+ Cl- cotransporters (KCCs) and Na+ K+ Cl- cotransporters (NKCCs)
		Expression
		Sequence homology
		Topological conservation
		Post-translational modifications
			Glycosylation
			Phosphorylation
			Cysteines conservation
	Topological conservation of K+ Cl- cotransporters (KCCs) and Na+ K+ Cl- cotransporters (NKCCs)
		Overall topology
		Topological organization of KCCs and NKCCs
		Structural homology
	Functional architecture of KCC2 and structural insights into ions transport
		Molecular structure of KCC2
		Role of the N and C-termini of KCC2
		Functional unit of KCC2
		Co-transporters oligomerization
		Current ions transport picture of NKCCs and KCCs
		Current insights into the ion transport mechanisms of CCC related transporters
		Molecular structure of NKCC1
		Molecular structure of KCC1 and structural comparison to NKCC1
	Conclusions and perspectives
	Acknowledgments
	References
Developmental expression of neuronal chloride transporters in different brain regions and sensory organs
	Neuronal chloride transporter family
	NKCC1 expression in the central nervous system
		Developmental expression of NKCC1 in rodents
		Developmental expression of NKCC1 in the human brain
	KCC expression in the central nervous system
		Developmental expression of KCC in rodents
			KCC1 expression patterns
			KCC2 expression patterns
			KCC3 expression patterns
			KCC4 expression patterns
		Developmental expression of KCC in the human brain
	Sex differences in NKCC1 and KCC2 expression
	Transient inhibitory switch in GABA signaling during the perinatal period
	NKCC1 and KCC2 expression in neuronal subtypes
	NKCC1 and KCC expression in sensory organs
		Pain and proprioception
		Olfactory system
		Auditory system
		Visual system
	Summary
	References
Post-translational modification of neuronal chloride transporters
	Introduction
	Post-translational modification of NKCC1 and KCC2
		Glycosylation
		Oligomerization
		Phosphorylation
		Degradation
	Conclusion
	References
Protein interaction partners of neuronal chloride transporters
	Introduction
	Experimental considerations to study native-CCC containing protein complexes
		Subcellular fractionation
		Solubilization parameters
		Target antibody
		Compiling the interactome
		Network mapping and functional analyses
	Molecular organization of the CCC-MPCs
		Composition of CCC-MPCs
		Transporter core and auxiliary subunits
		Supercomplexes and protein networks
	KCC2 interactome
		KCC2: Ion-pump supercomplex
			Na+/K+-ATPase
			CKB
		KCC2: GPCR supercomplex
			Gq-GPCRs-Group1 mGluRs, mKAR, and others
			Non-Gq-GPCRs-GABABR
		KCC2-kainate receptor chansporter supercomplex: GluK2, Neto2
		KCC2: Cytoskeletal network-4.1N, β-pix
		KCC2: Enzyme signaling supercomplex-Dynamic partners
			PKC, Src, PP1, calpain
			WNK, OSR, SPAK
		Other components of the KCC2 MPC
			APP
			AP2 and Rab11
			HTT
			Protein associated with Myc (PAM)
			Neuroligin2
		KCC2 functional proteomics
		PACSIN1
	Future directions
		Interactome of other CCCs in the CNS
		Emerging KCC2-chansporter complexes
			Other iGluRs
			GABAARs
			Calcium channels
			Potassium channels
		Emerging KCC2-cytoskeletal complexes
		Emerging KCC2 complexes with other ion pumps and transporters
		Examining KCC2 proteomics in distinct neuronal subtypes and non-neurons
	Conclusions
	References
	Further reading
Genetic and environmental regulators of Kcc2/KCC2 gene expression
	Introduction
	Chloride shift: Ontogenesis of Kcc2/KCC2 gene expression
	Signaling pathways and transcription factors that regulate Kcc2 gene expression
	Beyond the genome: Epigenetic regulation of Kcc2 gene expression
	Epilog
	References
	Further reading
The involvement of neuronal chloride transporter deficiencies in epilepsy
	Introduction
	KCC2 functional modulators in health and disease
	NKCC1 functional modulators in health and disease
	Acquired epilepsy
		Hypoxic-ischemic encephalopathy (HIE)
		Inflammation
		Traumatic brain injury
		Tumor-associated epilepsy
		Temporal lobe epilepsy
	Genetic epilepsies
		Rett syndrome
		Fragile X syndrome
		Down syndrome
		Alzheimer's disease
		Schizophrenia
	Conclusion
	References
The role of cation-chloride co-transporters in cardiovascular and respiratory abnormalities and SUDEP
	Introduction
	CCCs in heart
	Autonomic nervous system control of cardiac function
	CCC expression and function in vascular smooth muscle
	CCC function in blood pressure regulation
	CCC function in respiration
	CCCs in epilepsy and neurodevelopmental disease
	CCCs and sudden unexpected death in epilepsy
	References
Connecting chloride transporter impairment following perinatal brain injury to cerebral palsy
	Cerebral palsy
	Chloride transporters: Critical periods
		Motor impairment: Spasticity and hyperreflexia
		Chronic pain
		Cognition: Executive function and higher order processing
	Therapeutic targets
	Conclusion
	References
WNK-SPAK/OSR1-CCC signaling in ischemic brain damage
	Introduction
		Therapeutic status of ischemic stroke
		Ischemic core and penumbra
		Molecular mechanisms of stroke pathology
	Roles of NKCC1 in ischemic brain damage
		Roles of NKCC1 in the normal CNS
		Glutamate-mediated activation of NKCC1 contributes to neuronal damage
		NKCC1 in ionic dysregulation, swelling, and excitatory amino acid release in reactive astrocytes
		Blocking NKCC1 activity reduces brain damage in experimental ischemic stroke models
		NKCC1 activation in demyelination and white matter injury after ischemic stroke
	KCCs in the nervous system and disorders
		Roles of KCCs in the normal CNS
		Roles of KCCs in cerebral edema and damage
	WNK-SPAK/OSR1 signaling in ischemic brain damage
		WNK-SPAK/OSR1 kinases in the CNS
		Regulation of WNK-SPAK/OSR1-NKCC1 axis in experimental cerebral ischemic stroke
		WNK-SPAK/OSR1-mediated regulation of KCCs
		Pharmacological inhibition of WNK-SPAK/OSR1 signaling with novel inhibitors
		Developing WNK-SPAK binding disruptors
	Conclusion
	References
	Further reading
Role of chloride cotransporters in the development of spasticity and neuropathic pain after spinal cord injury
	Spinal cord development and chloride homeostasis
		Ventral white matter and motoneurons
		Dorsal horn neurons
		Spinal interneurons in intermediate gray
		DRG neurons and primary afferents
	Chloride homeostasis recapitulates development after SCI
	Functional consequences of a shift in chloride homeostasis after SCI
		Spasticity
		Central sensitization and chronic neuropathic pain
		Presynaptic inhibition
		Alteration in the locomotor pattern
	Regulation of CCCs after spinal cord injury
		PKC-dependent phosphorylation of KCC2
		BDNF-TrkB regulation of KCC2
		5-HT2A regulation of KCC2 activity
		Calpains-dependent cleavage of KCC2
		Reciprocal regulation of KCC2 and NKCC1 through WNK/SPAK/OSR1
		Neuron-glia interactions
		Others
	Promising treatments for spinal cord injury
		Activity-based therapies, rehabilitation and the BDNF pathway
		Blocking NKCC1 with bumetanide
		Enhancing KCC2 expression and extrusion capability
	Conclusion
	Acknowledgments
	References
Neuronal chloride homeostasis and nerve injury
	Peripheral nerve injury as a model and clinical conundrum
	Neuronal hyperexcitability: Is it only an unhappy accident?
	The mysterious shift in motoneuron excitability
	Excitatory and inhibitory synapses in regenerating motoneurons
	KCC2 depletion is the mechanism for altered inhibitory signaling in motoneurons
	Does inhibitory synaptic activity promote motor axon regeneration after PNI?
	Mammalian sensory neurons also become hyperexcitable and increase internal chloride after axotomy
	Injury-induced activation of synaptic and extrasynaptic chloride channels in sensory neurons
	Mammalian small sensory neurons embody the dual nature of changes in chloride
	Chloride regulation and development of a central hyperexcitable state contributing to pain, hyperalgesia, and allodynia
	Conclusions
	References
Disruptions in chloride transporter activity in autism spectrum disorders
	Developmental expression of NKCC1 and KCC2, and the GABA developmental sequence
	The oxytocin-mediated shift on intracellular chloride levels at birth
	Alterations of NKCC1 and KCC2 in autism, fragile X syndrome, maternal immune activation, and Rett syndrome
	Bumetanide treatment of autism spectrum disorders: Reducing [Cl-]i with an NKCC1 antagonist as a novel therapeutic avenue
	General conclusions
	Conflict of interest
	References
Chloride transporters in physiological brain development and neurodevelopmental disorders: The case of the Do ...
	Introduction
		Brain development and the role of GABA
	Chloride transporters in physiological brain development
		The role of NKCC1 and KCC2 in neuronal proliferation, migration, and network integration
			NKCC1 plays a key role in cell proliferation and apoptosis
			NKCC1 and KCC2 regulate neuronal migration
			NKCC1 and KCC2 regulate neuronal morphological maturation
		The role of NKCC1 and KCC2 in the critical period of brain plasticity
		Expression and role of other NKCCs and KCCs in the developing brain
	Chloride transporters in neurodevelopmental disorders
		Epilepsy
		Autism spectrum disorders
		Rett syndrome
		Fragile X syndrome
		Schizophrenia
		Tuberous sclerosis complex
		Neurodevelopmental abnormalities caused by traumatic brain injury
	Chloride transporters in Down syndrome
		Down syndrome and GABAergic transmission
		NKCC1 is implicated in depolarizing GABAAR signaling in Down syndrome
		Bumetanide treatment rescues the altered GABAergic transmission, synaptic plasticity and cognitive deficits in Ts65Dn mice
	Concluding remarks
	References
	Further reading
Alterations in chloride transporter activity in stress and depression
	Stress and chloride homeostasis
		Maternal stress and the developmental shift in chloride reversal potential
		Hippocampus
		Amygdala
		Bed nucleus of the stria terminalis (BnST)
		Ventral tegmental area (VTA)
		Spinal/supraspinal pathway
		Hypothalamus
	GABAergic hypothesis of depression
	Stress, HPA axis dysregulation, and depression
		Stress and depression
		HPA axis dysregulation and depression
		Chronic stress, chloride homeostasis, and HPA axis function
		KCC2, HPA axis, and postpartum depression
		KCC2, HPA axis, and comorbid depression in epilepsy
	Summary
	References
Neuronal chloride transporters in neurodegenerative diseases
	Introduction
	Mechanisms that control chloride (Cl-) homeostasis in neurons
		The transmembrane chloride gradient allows for neuronal inhibition by GABA
		Proteins that control the Cl- gradient in neurons
		Disruption of the chloride gradient in disease
		Themes of NKCC1/KCC2 regulation in disease
	Chloride transporters in epilepsy
		NKCC1/KCC2 imbalance leads to seizure
		Role of BDNF in epilepsy
		Genetic evidence links KCC2 with human epilepsy
	Chloride transporters in Alzheimer's disease
		Aberrant E/I occurred in both AD and epilepsy
		Abnormal BDNF may lead to altered chloride extrusion in aging and AD
		Regulation of KCC2 expression and function by APP
	Cl- homeostasis in Parkinson's disease
		Dopamine neurons extrude Cl- by a unique mechanism
		Cl- gradient alterations in non-dopaminergic cells in PD
		BDNF inhibits KCC2 expression to influence PD pathogenesis
		PD associated genetic mutations impact Cl- homeostasis
		Pharmacologic approaches to restore the Cl- gradient in PD
	Huntington's disease
		Cl- gradient homeostasis is disrupted in the striatum in HD
		Htt interacts with KCC2 to mediate toxicity in HD
		Htt regulates BDNF to influence KCC2 in HD
		Mutant Htt causes aberrant Cl- efflux in non-neuronal cells
	ALS causes altered Cl- gradients in motor neurons
	Concluding remarks
	Acknowledgments
	References
Gene therapy approaches to restore chloride homeostasis for treating neuropathic pain
	Introduction
	GABA and glycine disinhibition and chloride dysregulation in neuropathic pain
	Role of NMDA receptor-calpain signaling in nerve injury-induced KCC2 downregulation and neuropathic pain
	Gene therapy for neuropathic pain
	Conclusions and perspectives
	Acknowledgments
	References
Bumetanide to treat autism spectrum disorders: Clinical observations
	Introduction
	Clinical trials
	Brain functional imaging studies
	Discussion and general conclusions
	Conflict of interest
	References
	Further reading
Quest for pharmacological regulators of KCC2
	Introduction
		Structure-function relationship of KCC2: Molecular basis for the development of potent and selective KCC2-modulating compounds
		KCC2 in neurodevelopment: A pharmacological target with a ``timed´´ agenda
		From inhibition to excitation and back: The dynamic nature of KCC2 expression in the mature brain
		The ``fast´´ control of KCC2 activity: Post-translational modifications
	Conclusions and future directions
	Acknowledgment
	References
	Further reading
Index
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