The possible additional role of the cystic fibrosis transmembrane regulator to motoneuron inhibition produced by glycine effects

Morales, F.R.; Silveira, Valentina; Damián, Araceli; Higgie, R.; Pose, I.

doi:10.1016/j.neuroscience.2010.12.034

Cited by 10 publications

(10 citation statements)

References 40 publications

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“…However, even though the influence of CFTR on brain excitability is supported by little evidence, CFTR regulates a chloride channel, which is widely expressed in the brain cortex, diencephalon, midbrain, pons, and medulla oblongata . It has further been demonstrated that CFTR blockade produces impairment of glycine‐mediated inhibition of motor neurons, suggesting that CFTR may indeed regulate cortical inhibitory activity . Therefore, its alteration might produce a state of brain hyperexcitability and then generate a favorable ground for CSD occurrence.…”

Section: Discussionmentioning

confidence: 99%

Migrainous Infarction in a Patient With Sporadic Hemiplegic Migraine and Cystic Fibrosis: A 99mTc‐HMPAO Brain SPECT Study

et al. 2019

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Genetic mutations of sporadic hemiplegic migraine (SHM) are mostly unknown. SHM pathophysiology relies on cortical spreading depression (CSD), which might be responsible for ischemic brain infarction. Cystic fibrosis (CF) is caused by a monogenic mutation of the chlorine transmembrane conductance regulator (CFTR), possibly altering brain excitability. We describe the case of a patient with CF, who had a migrainous stroke during an SHM attack. A 32-year-old Caucasian male was diagnosed with CF, with heterozygotic delta F508/unknown CFTR mutation. The patient experiences bouts of coughing sometimes triggering SHM attacks with visual phosphenes, aphasia, right-sided paresthesia, and hemiparesis. He had a 48-hour hemiparesis triggered by a bout of coughing with hemoptysis, loss of consciousness, and severe hypoxia-hypercapnia. MRI demonstrated transient diffusion hyperintensity in the left frontal-parietal-occipital regions resulting in a permanent infarction in the primary motor area. Later, a brain perfusion SPECT showed persistent diffuse hypoperfusion in the territories involved in diffusion-weighted imaging alteration. Migrainous infarction, depending on the co-occurrence of 2 strictly related phenomena, CSD and hypoxia, appears to be the most plausible explanation. Brain SPECT hypoperfusion suggests a more extensive permanent neuronal loss in territories affected by aura. CF may be then a risk factor for hemiplegic migraine and stroke since bouts of coughing can facilitate brain hypoxia, triggering auras. Abbreviations: CF cystic fibrosis, CSD cortical spreading depression, DWI diffusion-weighted imaging, ED emergency department, FHM familial hemiplegic migraine, HM hemiplegic migraine, NSAID nonsteroidal antiinflammatory drugs, PFO patent foramen ovale, RCVS reversible cerebral vasoconstriction syndrome, SHM sporadic hemiplegic migraine (Headache 2019;59:253-258) Headache

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Section: Discussionmentioning

confidence: 99%

Migrainous Infarction in a Patient With Sporadic Hemiplegic Migraine and Cystic Fibrosis: A 99mTc‐HMPAO Brain SPECT Study

et al. 2019

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“…resting PKA activity levels may be relatively high in amacrine cells. Interestingly, two reports on the role of CFTR in neuronal cytosolic Cl Ϫ homeostasis demonstrate effects of CFTR inhibitors on cytosolic Cl Ϫ in the absence of stimulated PKA activity (Morales et al 2011;Ostroumov et al 2011), implying significant baseline CFTR (and possibly PKA) activity in those neurons. A third possibility is that the Ca 2ϩ elevations that we know are generated by NO in amacrine cells (Maddox and Gleason 2017) activate the Ca 2ϩ -sensitive adenylate cyclase, adenylate cyclase 1.…”

Section: Discussionmentioning

confidence: 99%

“…The limited number of functional studies in neurons demonstrate a role for CFTR in regulating cytosolic Cl Ϫ (Morales et al 2011;Ostroumov et al 2011), nonvesicular ATP release (Kanno and Nishizaki 2011), glucose sensing by hypothalamic neurons (Chalmers et al 2014;Murphy et al 2009), exocytosis (Weyler et al 1999), and peripheral nerve myelination (Reznikov et al 2013). In addition to its well-established expression at the plasma membrane, CFTR can be active in multiple acidic organelles, including the trans-Golgi (Barasch et al 1991), endosomes (Biwersi and Verkman 1994), and lysosomes (Liu et al 2012).…”

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confidence: 99%

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl⁻ from acidic organelles in amacrine cells

Krishnan

Maddox

Rodriguez

et al. 2017

Journal of Neurophysiology

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γ-Amino butyric acid (GABA) and glycine typically mediate synaptic inhibition because their ligand-gated ion channels support the influx of Cl However, the electrochemical gradient for Cl across the postsynaptic plasma membrane determines the voltage response of the postsynaptic cell. Typically, low cytosolic Cl levels support inhibition, whereas higher levels of cytosolic Cl can suppress inhibition or promote depolarization. We previously reported that nitric oxide (NO) releases Cl from acidic organelles and transiently elevates cytosolic Cl, making the response to GABA and glycine excitatory. In this study, we test the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in the NO-dependent efflux of organellar Cl We first establish the mRNA and protein expression of CFTR in our model system, cultured chick retinal amacrine cells. Using whole cell voltage-clamp recordings of currents through GABA-gated Cl channels, we examine the effects of pharmacological inhibition of CFTR on the NO-dependent release of internal Cl To interfere with the expression of CFTR, we used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing. We find that both pharmacological inhibition and CRISPR/Cas9-mediated knockdown of CFTR block the ability of NO to release Cl from internal stores. These results demonstrate that CFTR is required for the NO-dependent efflux of Cl from acidic organelles. Although CFTR function has been studied extensively in the context of epithelia, relatively little is known about its function in neurons. We show that CFTR is involved in an NO-dependent release of Cl from acidic organelles. This internal function of CFTR is particularly relevant to neuronal physiology because postsynaptic cytosolic Cl levels determine the outcome of GABA- and glycinergic synaptic signaling. Thus the CFTR may play a role in regulating synaptic transmission.

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“…Even if these symptoms may result from a complex association of diabetes, autoimmunity and vitamin deficiency, a primary CFTR defect is also likely to be involved as shown by the recent report of peripheral nervous system defects observed in CFTR -/-pigs at birth (Reznikov et al 2013). Concerning CFTR protein function, recent works have studied CFTR activity in motor neurons of the spinal cord or brainstem nuclei in rats during neonatal development (Ostroumov et al 2007;Morales et al 2011) and have shown that CFTR contributes to the relatively depolarized equilibrium potential for synaptic inhibition, an important process to control hyperexcitability and seizure-predisposition in neonates (Ostroumov et al 2007). It has also been shown that CFTR plays a role in postsynaptic inhibition of motor neurons from the trigeminal motor nucleus during rapid-eye-movement (REM) sleep (Morales et al 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Concerning CFTR protein function, recent works have studied CFTR activity in motor neurons of the spinal cord or brainstem nuclei in rats during neonatal development (Ostroumov et al 2007;Morales et al 2011) and have shown that CFTR contributes to the relatively depolarized equilibrium potential for synaptic inhibition, an important process to control hyperexcitability and seizure-predisposition in neonates (Ostroumov et al 2007). It has also been shown that CFTR plays a role in postsynaptic inhibition of motor neurons from the trigeminal motor nucleus during rapid-eye-movement (REM) sleep (Morales et al 2011). Recently, Ostroumov and colleagues observed that the gene activities of the chloride inward transporter, NKCC1, and CFTR were positively correlated postnatally and, using different blockers for these channels, demonstrated that inhibition of CFTR or NKCC1 activity produced a negative shift in GABA/glycine reversal potential of spontaneously occurring synaptic events measured after block of excitatory transmission, suggesting that CFTR operated together with NKCC1 to produce depolarizing GABA/glycinemediated synaptic events (Ostroumov et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) Expression in the Developing Human Brain

Marcorelles

Friocourt

Uguen

et al. 2014

J Histochem Cytochem.

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SummaryCystic Fibrosis Transmembrane conductance Regulator (CFTR) protein has recently been shown to be expressed in the human adult central nervous system (CNS). As CFTR expression has also been documented during embryonic development in several organs, such as the respiratory tract, the intestine and the male reproductive system, suggesting a possible role during development we decided to investigate the expression of CFTR in the human developing CNS. In addition, as some, although rare, neurological symptoms have been reported in patients with CF, we compared the expression of normal and mutated CFTR at several fetal stages. Immunohistochemistry was performed on brain and spinal cord samples of foetuses between 13 and 40 weeks of gestation and compared with five patients with cystic fibrosis (CF) of similar ages. We showed in this study that CFTR is only expressed in neurons and has an early and widespread distribution during development. Although we did not observe any cerebral abnormality in patients with CF, we observed a slight delay in the maturation of several brain structures. We also observed different expression and localization of CFTR depending on the brain structure or the cell maturation stage. Our findings, along with a literature review on the neurological phenotypes of patients with CF, suggest that this gene may play previously unsuspected roles in neuronal maturation or function. (J Histochem Cytochem 62:791-801, 2014)

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The possible additional role of the cystic fibrosis transmembrane regulator to motoneuron inhibition produced by glycine effects

Cited by 10 publications

References 40 publications

Migrainous Infarction in a Patient With Sporadic Hemiplegic Migraine and Cystic Fibrosis: A 99mTc‐HMPAO Brain SPECT Study

Migrainous Infarction in a Patient With Sporadic Hemiplegic Migraine and Cystic Fibrosis: A 99mTc‐HMPAO Brain SPECT Study

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl⁻ from acidic organelles in amacrine cells

Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) Expression in the Developing Human Brain

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The possible additional role of the cystic fibrosis transmembrane regulator to motoneuron inhibition produced by glycine effects

Cited by 10 publications

References 40 publications

Migrainous Infarction in a Patient With Sporadic Hemiplegic Migraine and Cystic Fibrosis: A 99mTc‐HMPAO Brain SPECT Study

Migrainous Infarction in a Patient With Sporadic Hemiplegic Migraine and Cystic Fibrosis: A 99mTc‐HMPAO Brain SPECT Study

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl− from acidic organelles in amacrine cells

Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) Expression in the Developing Human Brain

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A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl⁻ from acidic organelles in amacrine cells