Figure 1. Ca²⁺ sources influencing Ca_V2.1 opening.

A and B, Ca²⁺–CaM regulation of channels arises from a superposition of local and global Ca²⁺ sources. Ca_V2.1 channels stimulated by a voltage step give rise to Ca²⁺ current I, which is proportional to channel activation gating. The Ca²⁺ current, shaped by local diffusion and buffering, creates a local nanodomain Ca²⁺ signal that feeds into the CaM regulatory module, which bestows feedback modulation on activation gating. Concurrently, Ca²⁺ from distant channels shaped by cell diffusion and buffering creates a global Ca²⁺ signal which is also an input into the CaM regulatory module. C and D, simplified scheme employing Li⁺ as charge carrier. Stimulating Ca_V2.1 here gives rise to Li⁺ current I, which is allowed to reach steady state (steady gating) before Ca²⁺ is uncaged to influence the CaM regulatory module. Importantly, in this system, Ca²⁺ uncaging generates the only Ca²⁺ signal, which is spatially uniform and measurable.