BK(Ca) channel dysfunction in neurological diseases

The large conductance, Ca(2+)-activated K(+) channels (BK(Ca), K(Ca1.1)) are expressed in various brain neurons where they play important roles in regulating action potential duration, firing frequency and neurotransmitter release. Membrane potential depolarization and rising levels of intracellular Ca(2+) gated BK(Ca) channels, which in turn results in an outward K(+) flux that re/hyperpolarizes the membrane. The sensitivity of BK(Ca) channels to Ca(2+) provides an important negative-feedback system for Ca(2+) entry into brain neurons and suppresses repetitive firing. Thus, BK(Ca) channel loss-of-function gives rise to neuronal hyperexcitability, which can lead to seizures. Evidence also indicates that BK(Ca) channels can facilitate high-frequency firing (gain-of-function) in some brain neurons. Interestingly, both gain-of-function and loss-of-function mutations of genes encoding for various BK(Ca) channel subunits have been associated with the development of neuronal excitability disorders, such as seizure disorders. The role of BK(Ca) channels in the etiology of some neurological diseases raises the possibility that these channels can be used as molecular targets to prevent and suppress disease phenotypes.