NKCC1 [Neurosurgery Wiki]

This page is read only. You can view the source, but not change it. Ask your administrator if you think this is wrong.
====== NKCC1 ======

{{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/1tIHruhjOFoTDEhoM70lXYES1YUBsx46iay3FqoOItektH2gY2/?limit=15&utm_campaign=pubmed-2&fc=20240117033137}}

The [[Na-K-Cl cotransporter]] ([[NKCC]]) is a protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, [[NKCC1]] and NKCC2, encoded by two different genes (SLC12A2 and SLC12A1 respectively). Two isoforms of the NKCC1/Slc12a2 gene result from keeping (isoform 1) or skipping (isoform 2) exon 21 in the final gene product.
----
In some cases of [[epilepsy]], it has been observed that the expression or function of the [[NKCC1]] cotransporter in astrocytes and neurons may be altered. The NKCC1 cotransporter is responsible for importing [[chloride]] ions into cells, and increased activity of NKCC1 can result in elevated intracellular chloride levels. This, in turn, can lead to a shift in the GABAergic response from inhibitory to excitatory, a phenomenon known as "GABAergic depolarization."

GABAergic depolarization can contribute to hyperexcitability in the brain, potentially facilitating the generation and propagation of epileptic seizures. Astrocytes may modulate the expression and function of NKCC1, influencing chloride homeostasis and, consequently, the balance between excitatory and inhibitory neurotransmission
((Untiet V, Nedergaard M, Verkhratsky A. Astrocyte chloride, excitatory-inhibitory balance and epilepsy. Neural Regen Res. 2024 Sep 1;19(9):1887. doi: 10.4103/1673-5374.390981. Epub 2023 Dec 15. PMID: 38227511.))
----

With-no-[[lysine kinase]] ([[WNK]]) and Na+-K+-2Cl- cotransporter 1 ([[NKCC1]]) are involved in the pathogenesis of hypertension. In this study, we investigated the WNK-NKCC1 signaling pathway in spontaneously hypertensive rats (SHR) and their associated susceptibility to stroke injury. Basal NKCC1 protein levels were higher in SHR than in normotensive Wistar Kyoto (WKY) rat brains. After inducing ischemic stroke, adult male WKY and SHR received either saline or NKCC1 inhibitor bumetanide (10 mg/kg/day, i.p.) starting at 3-h post-reperfusion. NKCC1 inhibition blunted the extent of ischemic infarction in SHR and improved their neurobehavioral functions. Interestingly, ischemia led to increased NKCC1 phosphorylation in SHR but not in WKY rats. Pronounced elevation of WNK1, WNK2 and WNK4 protein and downregulation of WNK3 were detected in ischemic SHR, but not in ischemic WKY rats. Upregulation of WNK-NKCC1 complex in ischemic SHR brain was associated with increased Ca2+-binding protein 39 (Cab39), without increases in Ste20-related proline alanine-rich kinase or oxidative stress-responsive kinase-1. Moreover, subacute middle cerebral artery stroke human brain autopsy exhibited increased expression of NKCC1 protein. We conclude that augmented WNK-Cab39-NKCC1 signaling in SHR is associated with an increased susceptibility to ischemic brain damage and may serve as a novel target for anti-hypertensive and anti-ischemic stroke therapy.
----
A range of neurological pathologies may lead to secondary [[hydrocephalus]]. Treatment has largely been limited to surgical [[cerebrospinal fluid]] [[diversion]], as specific and efficient pharmacological options are lacking, partly due to the elusive molecular nature of the [[cerebrospinal fluid]]  [[secretion]] apparatus and its regulatory properties in [[physiology]] and [[pathophysiology]].

[[Cerebrospinal fluid]] obtained from patients with [[subarachnoid hemorrhage]] (SAH) and [[rat]]s with experimentally inflicted [[intraventricular hemorrhage]] (IVH) was analyzed for lysophosphatidic [[acid]] (LPA) by alpha-LISA. Toft-Bertelsen et al. employed the [[in vivo]] [[rat model]] to determine the effect of LPA on ventricular size and brain water content, and to reveal the effect of activation and inhibition of the transient receptor potential vanilloid 4 ([[TRPV4]]) ion channel on intracranial pressure and CSF secretion rate. LPA-mediated modulation of TRPV4 was determined with electrophysiology and an ex vivo radio-isotope assay was employed to determine the effect of these modulators on choroid plexus transport.

Elevated levels of LPA were observed in CSF obtained from patients with subarachnoid hemorrhage (SAH) and from rats with experimentally-inflicted intraventricular hemorrhage (IVH). Intraventricular administration of LPA caused elevated brain water content and [[ventriculomegaly]] in experimental rats, via its action as an agonist of the choroidal transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4 was revealed as a novel regulator of ICP in experimental rats via its ability to modulate the CSF secretion rate through its direct activation of the Na+/K+/2Cl- cotransporter (NKCC1) implicated in CSF secretion.

Together, these data reveal that a [[serum]] [[lipid]] present in brain pathologies with hemorrhagic events promotes CSF hypersecretion and ensuing brain water accumulation via its direct action on [[TRPV4]] and its downstream regulation of [[NKCC1]]. TRPV4 may therefore be a promising future pharmacological target for pathologies involving brain water accumulation
((Toft-Bertelsen TL, Barbuskaite D, Heerfordt EK, Lolansen SD, Andreassen SN, Rostgaard N, Olsen MH, Norager NH, Capion T, Rath MF, Juhler M, MacAulay N. [[Lysophosphatidic acid]] as a [[CSF]] [[lipid]] in [[posthemorrhagic hydrocephalus]] that drives CSF accumulation via [[TRPV4]]-induced hyperactivation of [[NKCC1]]. Fluids Barriers CNS. 2022 Sep 6;19(1):69. doi: 10.1186/s12987-022-00361-9. PMID: 36068581.)).