BK channel properties correlate with neurobehavioral severity in three -linked channelopathy mouse models.

KCNMA1 forms the pore of BK K channels, which regulate neuronal and muscle excitability. Recently, genetic screening identified heterozygous variants in a subset of patients with debilitating paroxysmal non-kinesigenic dyskinesia, presenting with or without epilepsy (PNKD3). However, the relevance of mutations and the basis for clinical heterogeneity in PNKD3 has not been established.

Comparative Ca channel contributions to intracellular Ca levels in the circadian clock.

Circadian rhythms in mammals are coordinated by the central clock in the brain, located in the suprachiasmatic nucleus (SCN). Multiple molecular and cellular signals display a circadian variation within SCN neurons, including intracellular Ca, but the mechanisms are not definitively established. SCN cytosolic Ca levels exhibit a peak during the day, when both action potential firing and Ca channel activity are increased, and are decreased at night, correlating with a reduction in firing rate.

Contributions of Ca1.3 Channels to Ca Current and Ca-Activated BK Current in the Suprachiasmatic Nucleus.

Daily regulation of Ca and voltage-activated BK K channel activity is required for action potential rhythmicity in the suprachiasmatic nucleus (SCN) of the hypothalamus, the brain's circadian clock. In SCN neurons, BK activation is dependent upon multiple types of Ca channels in a circadian manner. Daytime BK current predominantly requires Ca influx through L-type Ca channels (LTCCs), a time when BK channels are closely coupled with their Ca source.

BK channel activation by L-type Ca channels Ca1.2 and Ca1.3 during the subthreshold phase of an action potential.

Mammalian circadian (24 h) rhythms are timed by the pattern of spontaneous action potential firing in the suprachiasmatic nucleus (SCN). This oscillation in firing is produced through circadian regulation of several membrane currents, including large-conductance Ca- and voltage-activated K (BK) and L-type Ca channel (LTCC) currents. During the day steady-state BK currents depend mostly on LTCCs for activation, whereas at night they depend predominantly on ryanodine receptors (RyRs).

Ion Channels Controlling Circadian Rhythms in Suprachiasmatic Nucleus Excitability.

Animals synchronize to the environmental day-night cycle by means of an internal circadian clock in the brain. In mammals, this timekeeping mechanism is housed in the suprachiasmatic nucleus (SCN) of the hypothalamus and is entrained by light input from the retina. One output of the SCN is a neural code for circadian time, which arises from the collective activity of neurons within the SCN circuit and comprises two fundamental components: ) periodic alterations in the spontaneous excitability of individual neurons that result in higher firing rates during the day and lower firing rates at night, and ) synchronization of these cellular oscillations throughout the SCN.

Effects of Single Nucleotide Polymorphisms in Human on BK Current Properties.

BK Ca-activated K channels are important regulators of membrane excitability. Multiple regulatory mechanisms tailor BK current properties across tissues, such as alternative splicing, posttranslational modifications, and auxiliary subunits. Another potential mechanism for modulating BK channel activity is genetic variation due to single nucleotide polymorphisms (SNPs).

Diurnal properties of voltage-gated Ca currents in suprachiasmatic nucleus and roles in action potential firing.

Key Points: Circadian oscillations in spontaneous action potential firing in the suprachiasmatic nucleus (SCN) translate time-of-day throughout the mammalian brain. The ion channels that regulate the circadian pattern of SCN firing have not been comprehensively identified. Ca channels regulate action potential activity across many types of excitable cells, and the activity of L-, N-, P/Q- and R-type channels are required for normal daytime firing frequency in SCN neurons and circuit rhythms.