Modulation of Cav2.3 channels by unconjugated bilirubin (UCB) - Candidate mechanism for UCB-induced neuromodulation and neurotoxicity.
Mol Cell Neurosci
; 96: 35-46, 2019 04.
Article
en En
| MEDLINE
| ID: mdl-30877033
ABSTRACT
Elevated levels of unbound unconjugated bilirubin (UCB) can lead to bilirubin encephalopathy and kernicterus. In spite of a large number of studies demonstrating UCB-induced changes in central neurotransmission, it is still unclear whether these effects involve alterations in the function of specific ion channels. To assess how different UCB concentrations and UCBalbumin (U/A) molar ratios affect neuronal R-type voltage-gated Ca2+ channels, we evaluated their effects on whole-cell currents through recombinant Cav2.3â¯+â¯ß3 channel complexes and ex-vivo electroretinograms (ERGs) from wildtype and Cav2.3-deficient mice. Our findings show that modestly elevated levels of unbound UCB (U/Aâ¯=â¯0.5) produce subtle but significant changes in the voltage-dependence of activation and prepulse inactivation, resulting in a stimulation of currents activated by weak depolarization and inhibition at potentials on the plateau of the activation curve. Saturation of the albumin binding capacity (U/Aâ¯=â¯1) produced additional suppression that became significant when albumin was omitted completely and might involve a complete loss of channel function. Acutely administered UCB (U/Aâ¯=â¯0.5) has recently been shown to affect transsynaptic signaling in the isolated vertebrate retina. The present report reveals that sustained exposure of the murine retina to UCB significantly suppresses also late responses of the inner retina (b-wave) from wildtype compared to Cav2.3-deficient mice. In addition, recovery during washout was significantly more complete and faster in retinae lacking Cav2.3 channels. Together, these findings show that UCB affects cloned and native Cav2.3 channels at clinically relevant U/A molar ratios and indicate that supersaturation of albumin is not required for modulation but associated with a loss of channel functional that could contribute to chronic neuronal dysfunction.
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Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Retina
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Bilirrubina
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Canales de Calcio Tipo R
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Proteínas de Transporte de Catión
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Mol Cell Neurosci
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
Año:
2019
Tipo del documento:
Article