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bioRxiv · 10.1101/2024.03.11.584466

The Pannexin-1 N-terminal Helix Gates a Switch between Ion Conductance and Anandamide Transport

Anderson, C. L.·Weiilnger, N. L.·Visser, F.·Nielsen, A. C.·Boyce, A. K.·Thompson, R. J.
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Abstract

Anandamide is an endovanilloid and endocannabinoid with ligand activity at transient receptor potential vanilloid 1 channels and cannabinoid receptors, respectively. We have reported that block of Pannexin-1 channels in the CA1 hippocampus can increase concentrations of anandamide and induce presynaptic plasticity. It is not known how an ion channel can contribute to clearance of a lipid-derived signalling molecule. Here, we use electrophysiology and imaging of uptake of fluorescent anandamide to determine the structure-function relationship between the ion conduction and anandamide trasporter activities of pannexin-1. Expression of rat, mouse or human pannexin-1 in HEK cells caused a time dependent increase in anandamide uptake by all three orthologs. However, human pannexin-1 had reduced ion conduction. Low concentrations of anandamide augmented uptake of its fluorescent derivative, whereas higher concentrations competed, suggesting that anadamide may facilitate its own transport. Deletion of the N-terminal helix of pannexin-1 and the channel blocker, probenecid, blocked ion conduction but enhanced anandamide transport. In contrast, mutation of pore facing isoleucine 41 caused a gain of function in ion conduction with loss of anandamide transport. We conclude that the pannexin-1 channel is a dual ion channel / anandamide transporter and that these properties are gated by the channels N-terminal helix and likely linked to its presence or absence within the pore lining region.

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Anderson, C. L., Weiilnger, N. L., Visser, F., Nielsen, A. C., Boyce, A. K., Thompson, R. J.. 2024-03-13. The Pannexin-1 N-terminal Helix Gates a Switch between Ion Conductance and Anandamide Transport. https://doi.org/10.1101/2024.03.11.584466

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