Ca2+ channel nanodomains boost local Ca2+ amplitude

Local Ca2+ signals through voltage-gated Ca2+ channels (Ca(V)s) drive synaptic transmission, neural plasticity, and cardiac contraction. Despite the importance of these events, the fundamental relationship between flux through a single Ca-V channel and the Ca2+ signaling concentration within nanometers of its pore has resisted empirical determination, owing to limitations in the spatial resolution and specificity of fluorescence-based Ca2+ measurements. Here, we exploited Ca2+-dependent inactivation of Ca-V channels as a nanometer-range Ca2+ indicator specific to active channels. We observed an unexpected and dramatic boost in nanodomain Ca2+ amplitude, ten-fold higher than predicted on theoretical grounds. Our results uncover a striking feature of Ca-V nanodomains, as diffusion-restricted environments that amplify small Ca2+ fluxes into enormous local Ca2+ concentrations. This Ca2+ tuning by the physical composition of the nanodomain may represent an energy-efficient means of local amplification that maximizes information signaling capacity, while minimizing global Ca2+ load.