Spike Ca2+ influx upmodulates the spike afterdepolarization and bursting via intracellular inhibition of K(V)7/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(V)7 (KCNQ) channels. These channels generate the subthreshold, non-inactivating M-type K+ current, whose activation curtails the spike afterdepolarization. Inhibition of K(V)7/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.