(A) CaV1.2 channels are arranged into clusters in the PM of excitable cells; for simplicity, a cluster of two channels is shown. At the resting membrane potential (e.g., −80 mV), [Ca2+]i and CaV1.2 Po are low; hence, the majority of CaV1.2 channels are non-interacting. (B) During an action potential, the PM becomes depolarized, increasing the Po of independently gating CaV1.2 channels. Ca2+ flows into the cell through these active channels, producing an elevation in local [Ca2+]i and increasing Ca2+ binding to CaM. (C) Ca2+/CaM binding to the C-terminal pre-IQ domain of the CaV1.2 channel promotes physical interactions between adjacent channels. This functional coupling increases the activity of adjoined channels and thus amplifies Ca2+ influx. (D) CaV1.2 channels undergo VDI and CDI, and [Ca2+]i declines once more. However, the channels remain coupled in a ‘primed’, non-conducting state for a finite time. If the membrane is depolarized again when the channels are still primed, the amplification of Ca2+ influx will be immediate; otherwise, if [Ca2+]i remains at resting levels beyond the lifetime of the primed state, the coupling dissolves and the cycle begins again. (E) and (F) show proposed rate-dependent changes in CaV1.2 channel coupling in ventricular myocytes and neurons, respectively. Top: Simulated ventricular and neuronal action potentials are depicted at low, intermediate, and high firing rates. Bottom: The accompanying dynamic change in CaV1.2 channel coupling (reflected by FRET changes between adjacent channels). bpm, beats per minute; ips, impulses per second.