BKCa channel dysfunction in neurological diseases

The large conductance, Ca(2+)-activated K(+) channels (BKCa, KCa1.1) 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 BKCa channels, which in turn results in an outward K(+) flux that re/hyperpolarizes the membrane. The sensitivity of BKCa channels to Ca(2+) provides an important negative-feedback system for Ca(2+) entry into brain neurons and suppresses repetitive firing. Thus, BKCa channel loss-of-function gives rise to neuronal hyperexcitability, which can lead to seizures. Evidence also indicates that BKCa 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 BKCa channel subunits have been associated with the development of neuronal excitability disorders, such as seizure disorders. The role of BKCa 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.