Figure 6. Intracellular Zn²⁺‐induced Kv2.1 channel modulation occurs in compartmentalized signalling domains .

The results of the present study suggest that Zn²⁺ plays an early, critical role in Kv2.1 modulation. Transient surges in free Zn²⁺ concentration within the cell (either produced by exogenous ZnPyr treatment, as shown here, or induced by sublethal ischaemic injury), probably modulate neuronal RyR directly, inducing an increased Ca²⁺ event frequency. These Ca²⁺ transients, located in close proximity to Kv2.1 channel cluster domains, lead to calcineurin activation and subsequent Kv2.1 dephosphorylation and dispersal of channel localization. This signalling cascade is sensitive to Zn²⁺ chelation, calcineurin activation and RyR activity, with direct Zn²⁺‐modulation of RyR being the key link in this process between acute surges in intracellular Zn²⁺ and calcineurin‐mediated Kv2.1 modulation.