Spike Ca²⁺ influx upmodulates the spike afterdepolarization and bursting via intracellular inhibition of K_V7/M channels

In principal brain neurons, activation of Ca²⁺ channels during an action potential, or spike, causes Ca²⁺ entry into the cytosol within a millisecond. This in turn causes rapid activation of large conductance Ca²⁺-gated channels, which enhances repolarization and abbreviates the spike. Here we describe another remarkable consequence of spike Ca²⁺ entry: enhancement of the spike afterdepolarization. This action is also mediated by intracellular modulation of a particular class of K⁺ channels, namely by inhibition of K_V7 (KCNQ) channels. These channels generate the subthreshold, non-inactivating M-type K⁺ current, whose activation curtails the spike afterdepolarization. Inhibition of K_V7/M by spike Ca²⁺ entry allows the spike afterdepolarization to grow and can convert solitary spikes into high-frequency bursts of action potentials. Through this novel intracellular modulatory action, Ca²⁺ spike entry regulates the discharge mode and the signalling capacity of principal brain neurons.