Expanding Spectrum of Sodium Potassium Chloride Co-transporters in the Pathophysiology of Diseases

Abstract

Sodium potassium chloride co-transporter (NKCC) belongs to cation-dependent chloride co-transporter family, whose activation allows the entry of Na(+), K(+) and 2Cl(-) inside the cell. It acts in concert with K(+) Cl(-) co-transporter (KCC), which extrudes K(+) and Cl(-) ions from cell. NKCC1 is widely distributed throughout the body, while NKCC2 is exclusively present in kidney. Protein kinase A, protein kinase C, Ste20-related proline-alanine-rich kinase, oxidative stress responsive kinases, With No K=lysine kinase and protein phosphatase type 1 control the phosphorylation/dephosphorylation of key threonine residues of in regulatory domain of NKCC1. The selective inhibitors of NKCC1 including bumetanide and furosemide are conventionally employed as diuretics. However, recent studies have indicated that NKCC1 may be involved in the pathophysiology of anxiety, cerebral ischemia, epilepsy, neuropathic pain, fragile X syndrome, autism and schizophrenia. The inhibitors of NKCC1 are shown to produce anxiolytic effects; attenuate cerebral ischemia-induced neuronal injury; produce antiepileptic effects and attenuate neuropathic pain. In the early developing brain, GABAA activation primarily produces excitatory actions due to high NKCC1/KCC2 ratio. However, as the development progresses, the ratio of NKCC1/KCC2 ratio reverses and there is switch in the polarity of GABAA actions and latter acquires the inhibitory actions. The recapitulation of developmental-like state during pathological state may be associated with increase in the expression and functioning of NKCC1, which decreases the strength of inhibitory GABAergic neurotransmission. The present review describes the expanding role and mechanism of NKCC1 in the pathophysiology of different diseases.

Fig. (1)

The reversal of NKCC/KCC ratio decreases the inhibitory strength of GABAA signaling, which in turn leads to different pathological states.

Fig. (2)

Structure of NKCC1 with important binding sites for chloride ions and bumetanide along with important phosphorylation sites at the N terminal end of channel. NKCC1 is secondarily active transporter and is activated depending on sodium gradient created by Na⁺ K⁺ ATPase. The decrease in intracellular sodium activates NKCC1 which mediates transport of Na⁺, K⁺ and Cl- ions into the cell.

Fig. (3)

In the early developing brain, GABA primarily produces excitatory actions due to high NKCC1/KCC2 ratio. As a consequence, there is an increased intracellular Cl^-ions, which leads to depolarizing actions of GABA due to outward movement of Cl^- ions. However, as the development progresses, the ratio of NKCC1/KCC2 ratio reverses and there is switch in the polarity of GABA actions due to decreased intracellular Cl^- ions and GABA acquires inhibitory actions due to inward movement of Cl^- ions. The recapitulation of developmental-like state during pathological state may be associated with increase in the expression and functioning of NKCC1, which decreases the strength of inhibitory GABAergic neurotransmission.

Fig. (4)

Ischemicinjury causes stimulation of glutamate receptors which increases the release of Ca²⁺/CaM kinases and cAMP that enhances the expression of NKCC. Similarly p38 and MAP kinases activated due to ischemia that causes upregulation of NKCC. Ischemic injury also leads to down-regulation of DNA methyltransferases which causes increased expression of NKCC.

Fig. (5)

Epileptogenic stimuli enhance the expression of NKCC that causes intracellular accumulation of chloride ions which shift GABA mediated hyperpolarization to depolarization. Thus, depolarization lead to development of seizures. Also epileptogenic stimuli decreases the expression of KCC that causes intracellular accumulation of chloride ions lead to generation of osmotic gradient between intracellular and extracellular components. This gradient causes movement of fluid to intracellular components that decreases extracellular fluid fraction lead to seizure generation.

Fig. (6)

Nerve injury or inflammation causes activation of TRPV1 which causes activation of extracellular receptor kinases and Ca²⁺/CaM kinasesthat lead to the phosphorylation and activation of NKCC. On the other hand nerve injury or inflammation also causes stimulation of BDNF that activate tyrosine receptor B which decreases the expression of KCC. The increased expression of NKCC and reduced expression of KCC increases intracellular accumulation of chloride ions produces depolarization effect of GABA. Thus, GABA mediated depolarization causes stimulation of fiber Aβ that lead to generation of allodynia.