Reversible uncoupling of inactivation in N-type calcium channels

N-TYPE calcium channels are thought to be expressed specifically in neuronal cells^1-3 and to have a dominant role in the control of neurotransmitter release from sympathetic neurons^4,5. But their unitary properties are poorly understood and the separation of neuronal Ca²⁺ current into components carried by N-type or L-type Ca²⁺ channels is controversial⁶. Here we show that individual N-type Ca²⁺ channels in sympathetic neurons can carry two kineti-cally distinct components of current, one that is rapidly transient and one that is long lasting. The mechanism that gives rise to these two components is unexpected for Ca²⁺ channels: a test depolarization elicits either a rapidly inactivating, single short burst with an average duration of 40 ms, or sustained, non-inactivating channel activity lasting for over 1 s. The switching between inactivating and noninactivating activity is a slow process, the occurrence of each type of unitary kinetic behaviour remaining statistically correlated over several seconds. Variable coupling of inactivation in N-type Ca²⁺ channels could be an effective mechanism for the modulation of neuronal excitability and synaptic plasticity.