Altered trial-to-trial responses to reward outcomes in KCNMA1 knockout mice during probabilistic learning tasks.

The large-conductance calcium- and voltage-activated potassium (BK) channels, encoded by the KCNMA1 gene, play important roles in neuronal function. Mutations in KCNMA1 have been found in patients with various neurodevelopmental features, including intellectual disability, autism spectrum disorder (ASD), or attention deficit hyperactivity disorder (ADHD). Previous studies of KCNMA1 knockout mice have suggested altered activity patterns and behavioral flexibility, but it remained unclear whether these changes primarily affect immediate behavioral adaptation or longer-term learning processes.

Evaluation of four channelopathy variants on BK channel current under Ca1.2 activation.

Variants in , encoding the voltage- and calcium-activated K (BK) channel, are associated with human neurological disease. The effects of gain-of-function (GOF) and loss-of-function (LOF) variants have been predominantly studied on BK channel currents evoked under steady-state voltage and Ca conditions. However, in their physiological context, BK channels exist in partnership with voltage-gated Ca channels and respond to dynamic changes in intracellular Ca (Ca).

BK channel dysfunction disrupts attention-controlled behaviors and altered perseverative responses in murine instrumental learning.

This study examined the effect of knockout of KCNMA1 gene, coding for the BK channel, on cognitive and attentional functions in mice, with an aim to better understand its implications for human neurodevelopmental disorders. The study used the 3-choice serial reaction time task (3-CSRTT) to assess the learning performance, attentional abilities, and repetitive behaviors in mice lacking the KCNMA1 gene (KCNMA1) compared to wild-type (WT) controls. Results showed no significant differences in learning accuracy between the two groups.

Structural mapping of patient-associated KCNMA1 gene variants.

KCNMA1-linked channelopathy is a neurological disorder characterized by seizures, motor abnormalities, and neurodevelopmental disabilities. The disease mechanisms are predicted to result from alterations in KCNMA1-encoded BK K channel activity; however, only a subset of the patient-associated variants have been functionally studied. The localization of these variants within the tertiary structure or evaluation by pathogenicity algorithms has not been systematically assessed.

BK Channelopathies and -Linked Disease Models.

Novel variants encoding the BK K channel, are associated with a debilitating dyskinesia and epilepsy syndrome. Neurodevelopmental delay, cognitive disability, and brain and structural malformations are also diagnosed at lower incidence. More than half of affected individuals present with a rare negative episodic motor disorder, paroxysmal nonkinesigenic dyskinesia (PNKD3).

Disease-associated KCNMA1 variants decrease circadian clock robustness in channelopathy mouse models.

KCNMA1 encodes the voltage- and calcium-activated K+ (BK) channel, which regulates suprachiasmatic nucleus (SCN) neuronal firing and circadian behavioral rhythms. Gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity disrupt circadian behavior, but the effect of human disease-associated KCNMA1 channelopathy variants has not been studied on clock function. Here, we assess circadian behavior in two GOF and one LOF mouse lines.

Structural mapping of patient-associated gene variants.

KCNMA1-linked channelopathy is a neurological disorder characterized by seizures, motor abnormalities, and neurodevelopmental disabilities. The disease mechanisms are predicted to result from alterations in KCNMA1-encoded BK channel activity; however, only a subset of the patient-associated variants have been functionally studied. The localization of these variants within the tertiary structure or evaluation by pathogenicity algorithms has not been systematically assessed.

Effect of an autism-associated variant, G124R, on BK channel properties.

BK K channels are critical regulators of neuron and muscle excitability, comprised of a tetramer of pore-forming αsubunits from the gene and cell- and tissue-selective β subunits (). Mutations in are associated with neurological disorders, including autism. However, little is known about the role of neuronal BK channel β subunits in human neuropathology.

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.

Lisdexamfetamine Therapy in Paroxysmal Non-kinesigenic Dyskinesia Associated with the -N999S Variant.

Background: -linked channelopathy is a rare movement disorder first reported in 2005. Paroxysmal non-kinesigenic dyskinesia (PNKD) in -linked channelopathy is the most common symptom in patients harboring the -N999S mutation. PNKD episodes occur up to hundreds of times daily with significant morbidity and limited treatment options, often in the context of epilepsy.

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.

An emerging spectrum of variants and clinical features in -linked channelopathy.

-linked channelopathy is an emerging neurological disorder characterized by heterogeneous and overlapping combinations of movement disorder, seizure, developmental delay, and intellectual disability. encodes the BK K channel, which contributes to both excitatory and inhibitory neuronal and muscle activity. Understanding the basis of the disorder is an important area of active investigation; however, the rare prevalence has hampered the development of large patient cohorts necessary to establish genotype-phenotype correlations.

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).

Status Dystonicus, Oculogyric Crisis and Paroxysmal Dyskinesia in a 25 Year-Old Woman with a Novel Variant, K457E.

The diagnosis of a paroxysmal dyskinesia is difficult and status dystonicus is a rare life threatening movement disorder characterised by severe, frequent or continuous episodes of dystonic spasms. A 25 year old woman with chronic ataxia and paroxysmal dyskinesia presented with facial twitching, writhing of arms, oculogyric crisis and visual and auditory hallucinations. She developed respiratory failure and was ventilated.

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.

Comparative gain-of-function effects of the -N999S mutation on human BK channel properties.

, encoding the voltage- and calcium-activated potassium channel, has a pivotal role in brain physiology. Mutations in are associated with epilepsy and/or dyskinesia (PNKD3). Two mutations correlated with these phenotypes, D434G and N999S, were previously identified as producing gain-of-function (GOF) effects on BK channel activity.

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).

-linked channelopathy.

encodes the pore-forming α subunit of the "Big K" (BK) large conductance calcium and voltage-activated K channel. BK channels are widely distributed across tissues, including both excitable and nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility.

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.

Expression and Activation of BK Channels in Mice Protects Against Ischemia-Reperfusion Injury of Isolated Hearts by Modulating Mitochondrial Function.

Activation and expression of large conductance calcium and voltage-activated potassium channel (BK) by pharmacological agents have been implicated in cardioprotection from ischemia-reperfusion (IR) injury possibly by regulating mitochondrial function. Given the non-specific effects of pharmacological agents, it is not clear whether activation of BK is critical to cardioprotection. In this study, we aimed to decipher the mechanistic role of BK in cardioprotection from IR injury by genetically activating BK channels.

Glutamate-activated BK channel complexes formed with NMDA receptors.

The large-conductance calcium- and voltage-activated K (BK) channel has a requirement of high intracellular free Ca concentrations for its activation in neurons under physiological conditions. The Ca sources for BK channel activation are not well understood. In this study, we showed by coimmunopurification and colocalization analyses that BK channels form complexes with NMDA receptors (NMDARs) in both rodent brains and a heterologous expression system.

Differential contribution of Ca sources to day and night BK current activation in the circadian clock.

Large conductance K (BK) channels are expressed widely in neurons, where their activation is regulated by membrane depolarization and intracellular Ca (Ca). To enable this regulation, BK channels functionally couple to both voltage-gated Ca channels (VGCCs) and channels mediating Ca release from intracellular stores. However, the relationship between BK channels and their specific Ca source for particular patterns of excitability is not well understood.

The non-diuretic hypotensive effects of thiazides are enhanced during volume depletion states.

Thiazide derivatives including Hydrochlorothiazide (HCTZ) represent the most common treatment of mild to moderate hypertension. Thiazides initially enhance diuresis via inhibition of the kidney Na+-Cl- Cotransporter (NCC). However, chronic volume depletion and diuresis are minimal while lowered blood pressure (BP) is maintained on thiazides.