Modulation of Cav2.3 channels by unconjugated bilirubin (UCB) – Candidate mechanism for UCB-induced neuromodulation and neurotoxicity

Albanna, Walid; Lüke, Jan Niklas; Schubert, Gerrit Alexander; Dibué-Adjei, Maxine; Kotliar, Konstantin; Hescheler, Jürgen; Clusmann, Hans; Steiger, Hans‐Jakob; Hänggi, Daniel; Kamp, Marcel A.; Schneider, Toni; Neumaier, Felix

doi:10.1016/j.mcn.2019.03.003

Cited by 9 publications

(8 citation statements)

References 57 publications

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“…We focused on bilirubin ( Geerts et al, 2008 ) and angiotensin II ( Grace et al, 2012 ), which are known to be increased in the blood in cirrhosis. Bilirubin regulates the expression and activity of voltage-dependent Na + channels ( Shi et al, 2019 ), epithelial Na + channels ( Xue-Ping Wang et al, 2019 ), acid-sensing ion channels (ASICs) ( Lai et al, 2020 ), and VDCCs ( Liang et al, 2017 ; Albanna et al, 2019 ). Although we examined the effects of bilirubin on the expression and activity of TMEM16A channels, it had no effects in PVSMCs.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Ca2+-Activated Cl− Channel TMEM16A Mediated by Angiotensin II in Cirrhotic Portal Hypertensive Mice

et al. 2022

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Portal hypertension is defined as an increased pressure in the portal venous system and occurs as a major complication in chronic liver diseases. The pathological mechanism underlying the pathogenesis and development of portal hypertension has been extensively investigated. Vascular tone of portal vein smooth muscles (PVSMs) is regulated by the activities of several ion channels, including Ca2+-activated Cl− (ClCa) channels. TMEM16A is mainly responsible for ClCa channel conductance in vascular smooth muscle cells, including portal vein smooth muscle cells (PVSMCs). In the present study, the functional roles of TMEM16A channels were examined using two experimental portal hypertensive models, bile duct ligation (BDL) mice with cirrhotic portal hypertension and partial portal vein ligation (PPVL) mice with non-cirrhotic portal hypertension. Expression analyses revealed that the expression of TMEM16A was downregulated in BDL-PVSMs, but not in PPVL-PVSMs. Whole-cell ClCa currents were smaller in BDL-PVSMCs than in sham- and PPVL-PVSMCs. The amplitude of spontaneous contractions was smaller and the frequency was higher in BDL-PVSMs than in sham- and PPVL-PVSMs. Spontaneous contractions sensitive to a specific inhibitor of TMEM16A channels, T16Ainh-A01, were reduced in BDL-PVSMs. Furthermore, in normal PVSMs, the downregulation of TMEM16A expression was mimicked by the exposure to angiotensin II, but not to bilirubin. This study suggests that the activity of ClCa channels is attenuated by the downregulation of TMEM16A expression in PVSMCs associated with cirrhotic portal hypertension, which is partly mediated by increased angiotensin II in cirrhosis.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Ca2+-Activated Cl− Channel TMEM16A Mediated by Angiotensin II in Cirrhotic Portal Hypertensive Mice

et al. 2022

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“…There are more P/Q-subtype calcium channels in neonatal neurons than at more mature stages, thus subtype-specific increase of P/Q-type Ca2+ currents may be involved the vulnerability of neurons to bilirubin toxicity in auditory as well as other brain regions (413). A role for Ca 2+ channels in bilirubin neurotoxicity was also supported by studies of recombinant Ca v 2.3 + β 3 channel complexes and ex vivo electroretinograms from wildtype and Ca v 2.3-deficient mice (12). Thus, 10 µM UB produced changes in the voltage-dependence of activation and prepulse inactivation.…”

Section: Membrane Effectsmentioning

confidence: 88%

Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn

Hansen

Wong

Stevenson

2020

Physiological Reviews

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Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity.

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“…These numbers are in line with our choice of bilirubin concentrations for its acute actions. Our study differs in its objective and experimental paradigms from others that focus on the chronic effects of bilirubin by using lower doses for extended periods 26,27 .…”

Section: Discussionmentioning

confidence: 99%

Ca2+-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity

et al. 2019

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Neonatal jaundice is prevalent among newborns and can lead to severe neurological deficits, particularly sensorimotor dysfunction. Previous studies have shown that bilirubin (BIL) enhances the intrinsic excitability of central neurons and this can potentially contribute to their overexcitation, Ca2+ overload, and neurotoxicity. However, the cellular mechanisms underlying elevated neuronal excitability remain unknown. By performing patch-clamp recordings from neonatal neurons in the rat medial vestibular nucleus (MVN), a crucial relay station for locomotor and balance control, we found that BIL (3 μM) drastically increases the spontaneous firing rates by upregulating the current-mediated voltage-gated sodium channels (VGSCs), while shifting their voltage-dependent activation toward more hyperpolarized potentials. Immunofluorescence labeling and western immunoblotting with an anti-NaV1.1 antibody, revealed that BIL elevates the expression of VGSCs by promoting their recruitment to the membrane. Furthermore, we found that this VGSC-trafficking process is Ca2+ dependent because preloading MVN neurons with the Ca2+ buffer BAPTA-AM, or exocytosis inhibitor TAT-NSF700, prevents the effects of BIL, indicating the upregulated activity and density of functional VGSCs as the core mechanism accountable for the BIL-induced overexcitation of neonatal neurons. Most importantly, rectification of such overexcitation with a low dose of VGSC blocker lidocaine significantly attenuates BIL-induced cell death. We suggest that this enhancement of VGSC currents directly contributes to the vulnerability of neonatal brain to hyperbilirubinemia, implicating the activity and trafficking of NaV1.1 channels as a potential target for neuroprotection in cases of severe jaundice.

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Modulation of Cav2.3 channels by unconjugated bilirubin (UCB) – Candidate mechanism for UCB-induced neuromodulation and neurotoxicity

Cited by 9 publications

References 57 publications

Downregulation of Ca2+-Activated Cl− Channel TMEM16A Mediated by Angiotensin II in Cirrhotic Portal Hypertensive Mice

Downregulation of Ca2+-Activated Cl− Channel TMEM16A Mediated by Angiotensin II in Cirrhotic Portal Hypertensive Mice

Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn

Ca2+-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity

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