HepaCAM associates with connexin 43 and enhances its localization in cellular junctions

Wu, Meihui; Moh, Mei Chung; Schwarz, Herbert

doi:10.1038/srep36218

Cited by 30 publications

(42 citation statements)

References 27 publications

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“…These include, among others, the Na + /K + ‐ATPase, TRPV4, caveolin‐1 and Kir4.1 . Furthermore, recently an interaction of GlialCAM with connexin‐43 was described . These findings underline the potential importance of MLC1 and GlialCAM for brain ion and water homeostasis.…”

Section: Mlc1 and Glialcammentioning

confidence: 85%

Genetic defects disrupting glial ion and water homeostasis in the brain

Min

Knaap

2018

Brain Pathology

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Electrical activity of neurons in the brain, caused by the movement of ions between intracellular and extracellular compartments, is the basis of all our thoughts and actions. Maintaining the correct ionic concentration gradients is therefore crucial for brain functioning. Ion fluxes are accompanied by the displacement of osmotically obliged water. Since even minor brain swelling leads to severe brain damage and even death, brain ion and water movement has to be tightly regulated. Glial cells, in particular astrocytes, play a key role in ion and water homeostasis. They are endowed with specific channels, pumps and carriers to regulate ion and water flow. Glial cells form a large panglial syncytium to aid the uptake and dispersal of ions and water, and make extensive contacts with brain fluid barriers for disposal of excess ions and water. Genetic defects in glial proteins involved in ion and water homeostasis disrupt brain functioning, thereby leading to neurological diseases. Since white matter edema is often a hallmark disease feature, many of these diseases are characterized as leukodystrophies. In this review we summarize our current understanding of inherited glial diseases characterized by disturbed brain ion and water homeostasis by integrating findings from MRI, genetics, neuropathology and animal models for disease. We discuss how mutations in different glial proteins lead to disease, and highlight the similarities and differences between these diseases. To come to effective therapies for this group of diseases, a better mechanistic understanding of how glial cells shape ion and water movement in the brain is crucial.

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Section: Mlc1 and Glialcammentioning

confidence: 85%

Genetic defects disrupting glial ion and water homeostasis in the brain

Min

Knaap

2018

Brain Pathology

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“…Similarly, Cx43 has been shown to interact with GlialCAM and to depend on GlialCAM to be correctly targeted to the membrane (Wu et al 2016). Thus, between P10 and P15, GlialCAM might be necessary to drive the polarized localization of several astrocyte perivascular endfeet proteins.…”

Section: Discussionmentioning

confidence: 99%

Postnatal development of the astrocyte perivascular MLC1/GlialCAM complex defines a temporal window for the gliovascular unit maturation

et al. 2019

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Astrocytes, the most abundant glial cells of the central nervous system are morphologically complex. They display numerous processes interacting with synapses and blood vessels. At the vascular interface, astrocyte endfeet-terminated processes almost entirely cover the blood vessel surface and participate to the gliovascular unit where important vascular properties of the brain are set such as the blood-brain barrier (BBB) integrity. How specific morphological and functional interactions between astrocytes and the vascular compartment develop has not been fully investigated. Here, we elaborated an original experimental strategy to study the postnatal development of astrocyte perivascular endfeet. Using purified gliovascular units, we focused on the postnatal expression of MLC1 and GlialCAM, two transmembrane proteins forming a complex enriched at the junction between mature astrocyte perivascular endfeet. We showed that MLC1 and GlialCAM were enriched and assembled into mature complexes in astrocyte perivascular endfeet between postnatal days 10 and 15, after the formation of astrocyte perivascular Aquaporin 4 water channels. These events correlated with the increased expression of Claudin-5 and P-gP, two endothelial-specific BBB components. These results illustrate for the first time that astrocyte perivascular endfeet differentiation is a complex and progressive process which correlates with BBB maturation. Moreover, our results suggest that maturation of the astrocyte endfeet MLC1/GlialCAM complex between postnatal days 10 and 15 might be a key event in the gliovascular unit maturation.

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“…K + homeostasis is tightly linked to the homeostasis of other ions, and MLC1 and GlialCAM colocalize and/or interact with several proteins involved in ion and water homeostasis. This includes the dystrophin glycoprotein complex,5, 45 Na + /K + ‐ATPase,46 the swelling‐sensitive cation channel, TRPV4,47 and the gap‐junction protein, connexin 43 20. MLC1 and GlialCAM may therefore play a central role in organizing these components necessary for astrocyte ion and water homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Disruption of proteins important for this process, such as Kir4.1 K + channels,15, 16 glial gap‐junction proteins,17 and the astrocytic water channel aquaporin‐4 (AQP4),18 lead to impaired [K + ] o clearance and to epileptiform brain activity or an altered seizure threshold. MLC1 and GlialCAM undergo molecular interactions with several of these proteins 19, 20. Therefore, we hypothesize that defective astrocyte volume regulation in MLC leads to impaired control of [K + ] o ,8 resulting in hyperexcitability of neuronal networks and epilepsy.…”

mentioning

confidence: 98%

Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

Dubey

Brouwers

Hamilton

et al. 2018

Annals of Neurology

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ObjectiveLoss of function of the astrocyte‐specific protein MLC1 leads to the childhood‐onset leukodystrophy “megalencephalic leukoencephalopathy with subcortical cysts” (MLC). Studies on isolated cells show a role for MLC1 in astrocyte volume regulation and suggest that disturbed brain ion and water homeostasis is central to the disease. Excitability of neuronal networks is particularly sensitive to ion and water homeostasis. In line with this, reports of seizures and epilepsy in MLC patients exist. However, systematic assessment and mechanistic understanding of seizures in MLC are lacking.MethodsWe analyzed an MLC patient inventory to study occurrence of seizures in MLC. We used two distinct genetic mouse models of MLC to further study epileptiform activity and seizure threshold through wireless extracellular field potential recordings. Whole‐cell patch‐clamp recordings and K+‐sensitive electrode recordings in mouse brain slices were used to explore the underlying mechanisms of epilepsy in MLC.ResultsAn early onset of seizures is common in MLC. Similarly, in MLC mice, we uncovered spontaneous epileptiform brain activity and a lowered threshold for induced seizures. At the cellular level, we found that although passive and active properties of individual pyramidal neurons are unchanged, extracellular K+ dynamics and neuronal network activity are abnormal in MLC mice.InterpretationDisturbed astrocyte regulation of ion and water homeostasis in MLC causes hyperexcitability of neuronal networks and seizures. These findings suggest a role for defective astrocyte volume regulation in epilepsy. Ann Neurol 2018;83:636–649

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HepaCAM associates with connexin 43 and enhances its localization in cellular junctions

Cited by 30 publications

References 27 publications

Genetic defects disrupting glial ion and water homeostasis in the brain

Genetic defects disrupting glial ion and water homeostasis in the brain

Postnatal development of the astrocyte perivascular MLC1/GlialCAM complex defines a temporal window for the gliovascular unit maturation

Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

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