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bioRxiv · 10.1101/2022.05.06.490928

Insulin docking within the open hemichannel of connexin 43 may reduce risk of amyotrophic lateral sclerosis

Lehrer, S.·Rheinstein, P. H.
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Abstract

BackgroundType 2 diabetes (T2D), characterized by hyperinsulinemia, protects motor neurons against amyotrophic lateral sclerosis (ALS). Type 1 diabetes and a total lack of insulin are associated with increased risk of ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open pore via which toxic substances from the astrocytes reach the motor neurons. MethodsIn the current study we performed molecular docking of insulin with monomeric Cx31, monomeric Cx43, and hexameric Cx31 to assess whether insulin might affect the pore. Hexameric Cx31 and hexameric Cx43 have hemichannels composed of 6 subunits that work as transmembrane channels, binding together to form gap junction intercellular channels that open and close. We used the program AutoDock Vina Extended for the molecular docking study. ResultsCx31 shares amino acid and structural similarity to Cx43 and insulin docks to the same position of the N-terminal domain of monomeric Cx31 and monomeric Cx43. Insulin docks within the open hemichannel of hexameric Cx31, potentially blocking it. The block may be responsible for the protective relationship of T2D to ALS. ConclusionInsulin, especially intranasal insulin, might be a treatment for ALS. An insulin secretogogue such as oral sulfonylurea or glinide might also be of value.

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Lehrer, S., Rheinstein, P. H.. 2022-05-06. Insulin docking within the open hemichannel of connexin 43 may reduce risk of amyotrophic lateral sclerosis. https://doi.org/10.1101/2022.05.06.490928

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