Dataset Information

Unconjugated bilirubin modulates neuronal signaling only in wild-type mice, but not after ablation of the R-type/Ca_v 2.3 voltage-gated calcium channel.

ABSTRACT:

Introduction

The relationship between blood metabolites and hemoglobin degradation products (BMHDPs) formed in the cerebrospinal fluid and the development of vasospasm and delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) has been the focus of several previous studies, but their molecular and cellular targets remain to be elucidated.

Methods

Because BMHDP-induced changes in Ca_v 2.3 channel function are thought to contribute to DCI after aSAH, we studied their modulation by unconjugated bilirubin (UCB) in an organotypical neuronal network from wild-type (WT) and Ca_v 2.3-deficient animals (KO). Murine retinae were isolated from WT and KO and superfused with nutrient solution. Electroretinograms were recorded before, during, and after superfusion with UCB. Transretinal signaling was analyzed as b-wave, implicit time, and area under the curve (AUC).

Results

Superfusion of UCB significantly attenuated the b-wave amplitude in the isolated retina from wild-type mice by 14.9% (P < 0.05), followed by gradual partial recovery (P = 0.09). Correspondingly, AUC decreased significantly with superfusion of UCB (P < 0.05). During washout, the b-wave amplitude returned to baseline (P = 0.2839). The effects of UCB were absent in Ca_v 2.3-deficient mice, lacking the expression of Ca_v 2.3 as proofed on the biochemical level.

Conclusions

Ex vivo neuronal recording in the murine retina is able to detect transient impairment of transretinal signaling by UCB in WT, but not in KO. This new model may be useful to further clarify the role of calcium channels in neuronal signal alteration in the presence of BHMDPs.

SUBMITTER: Albanna W

PROVIDER: S-EPMC6489700 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Publications

Unconjugated bilirubin modulates neuronal signaling only in wild-type mice, but not after ablation of the R-type/Ca<sub>v</sub> 2.3 voltage-gated calcium channel.

Albanna Walid W Neumaier Felix F Lüke Jan Niklas JN Kotliar Konstantin K Conzen Catharina C Lindauer Ute U Hescheler Jürgen J Clusmann Hans H Schneider Toni T Schubert Gerrit Alexander GA

CNS neuroscience & therapeutics 20171223 3

<h4>Introduction</h4>The relationship between blood metabolites and hemoglobin degradation products (BMHDPs) formed in the cerebrospinal fluid and the development of vasospasm and delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) has been the focus of several previous studies, but their molecular and cellular targets remain to be elucidated.<h4>Methods</h4>Because BMHDP-induced changes in Ca<sub>v</sub> 2.3 channel function are thought to contribute to DCI after aSA ...[more]

PMID: 29274300

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Project description:Voltage-gated Cav1.2 and Cav1.3 (L-type) Ca2+ channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca2+-dependent facilitation of voltage-gated Cav1.3 Ca2+ channels in transfected cells. Mice lacking densin (densin KO) exhibit defects in synaptic plasticity, spatial memory, and increased anxiety-related behaviors-phenotypes that more closely match those in mice lacking Cav1.2 than Cav1.3. Therefore, we investigated the functional impact of densin on Cav1.2. We report that densin is an essential regulator of Cav1.2 in neurons, but has distinct modulatory effects compared with its regulation of Cav1.3. Densin binds to the N-terminal domain of Cav1.2, but not that of Cav1.3, and increases Cav1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Cav1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Cav1.2 channels, overexpression of densin increases the clustering of Cav1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Cav1.2 in the brain, as well as Cav1.2 current density and signaling to the nucleus, are reduced in neurons from densin KO mice. We conclude that densin is an essential regulator of neuronal Cav1 channels and ensures efficient Cav1.2 Ca2+ signaling at excitatory synapses.SIGNIFICANCE STATEMENT The number and localization of voltage-gated Cav Ca2+ channels are crucial determinants of neuronal excitability and synaptic transmission. We report that the protein densin-180 is highly enriched at excitatory synapses in the brain and enhances the cell surface trafficking and postsynaptic localization of Cav1.2 L-type Ca2+ channels in neurons. This interaction promotes coupling of Cav1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Cav1.2 in regulating cognition and mood.

Dataset Information

Unconjugated bilirubin modulates neuronal signaling only in wild-type mice, but not after ablation of the R-type/Ca_v 2.3 voltage-gated calcium channel.

Introduction

Methods

Results

Conclusions

Publications

Unconjugated bilirubin modulates neuronal signaling only in wild-type mice, but not after ablation of the R-type/Ca<sub>v</sub> 2.3 voltage-gated calcium channel.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Unconjugated bilirubin modulates neuronal signaling only in wild-type mice, but not after ablation of the R-type/Cav 2.3 voltage-gated calcium channel.

Introduction

Methods

Results

Conclusions

Publications

Unconjugated bilirubin modulates neuronal signaling only in wild-type mice, but not after ablation of the R-type/Ca<sub>v</sub> 2.3 voltage-gated calcium channel.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Unconjugated bilirubin modulates neuronal signaling only in wild-type mice, but not after ablation of the R-type/Ca_v 2.3 voltage-gated calcium channel.