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Neural circuits are endowed with several forms of intrinsic and synaptic plasticity that could contribute to adaptive changes in behavior, but circuit complexities have hindered linking specific cellular mechanisms with their behavioral consequences. Eye movements generated by simple brainstem circuits provide a means for relating cellular plasticity to behavioral gain control. Here we show that firing rate potentiation, a form of intrinsic plasticity mediated by reductions in BK-type calcium-activated potassium currents in spontaneously firing neurons, is engaged during optokinetic reflex compensation for inner ear dysfunction. Vestibular loss triggers transient increases in postsynaptic excitability, occlusion of firing rate potentiation, and reductions in BK currents in vestibular nucleus neurons. Concurrently, adaptive increases in visually evoked eye movements rapidly restore oculomotor function in wild-type mice but are profoundly impaired in BK channel-null mice. Activity-dependent regulation of intrinsic excitability may be a general mechanism for adaptive control of behavioral output in multisensory circuits.

Novel KCNMA1 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). The mechanistic relationship of PNKD3 to epilepsy and the broader spectrum of KCNMA1-associated symptomology is unknown. This review summarizes patient-associated KCNMA1 variants within the BK channel structure, functional classifications, genotype-phenotype associations, disease models, and treatment. Patient and transgenic animal data suggest delineation of gain-of-function (GOF) and loss-of-function KCNMA1 neurogenetic disease, validating two heterozygous alleles encoding GOF BK channels (D434G and N999S) as causing seizure and PNKD3. This discovery led to a variant-defined therapeutic approach for PNKD3, providing initial insight into the neurological basis. A comprehensive clinical definition of monogenic KCNMA1-linked disease and the neuronal mechanisms currently remain priorities for continued investigation. [ABSTRACT FROM AUTHOR]

In urinary bladder smooth muscle (UBSM), stimulation of [beta]-adrenergic receptors ([beta]-ARs) leads to activation of the large-conductance [Ca.sup.2+]-activated [K.sup.+] (BK) channel currents (Petkov GV and Nelson MT. Am J Physiol Cell Physiol 288: C1255-C1263, 2005). In this study we tested the hypothesis that the BK channel mediates UBSM relaxation in response to [beta]-AR stimulation using the highly specific BK channel inhibitor iberiotoxin (IBTX) and a BK channel knockout (BK-KO) mouse model in which the gene for the pore-forming subunit was deleted. UBSM strips isolated from wild-type (WT) and BK-KO mice were stimulated with 20 mM [K.sup.+] or [micro]M carbachol to induce phasic and tonic contractions. BK-KO and WT UBSM strips pretreated with IBTX had increased overall contractility, and UBSM BK-KO cells were depolarized with ~12 mV. Isoproterenol, a nonspecific [beta]-AR agonist, and forskolin, an adenylate cyclase activator, decreased phasic and tonic contractions of WT UBSM strips in a concentration-dependent manner. In the presence of IBTX, the concentrationresponse curves to isoproterenol and forskolin were shifted to the right in WT UBSM strips. Isoproterenol-and forskolin-mediated relaxations were enhanced in BK-KO UBSM strips, and a leftward shift in the concentration-response curves was observed. The leftward shift was eliminated upon PKA inhibition with H-89, suggesting up-regulation of the [beta]-AR-cAMP pathway in BK-KO mice. These results indicate that the BK channel is a key modulator in [beta]-AR-mediated relaxation of UBSM and further suggest that alterations in BK channel expression or function could contribute to some pathophysiological conditions such as overactive bladder and urinary incontinence. BK channel knockout mouse; isoproterenol; forskolin; iberiotoxin

Erectile dysfunction (ED) can be elicited by a variety of pathogenic factors, particularly impaired formation of and responsiveness to nitric oxide (NO) and the down-stream effectors soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI). One important target of PKGI in smooth muscle is the large-conductance, [Ca.sup.2+]-activated potassium ([BK.sub.Ca]) channel. In our previous report (42), we demonstrated that deletion of the [BK.sub.Ca] channel in mice induced force oscillations and led to reduced nerve-evoked relaxations and ED. In the current study, we used this ED model to explore the role of the [BK.sub.Ca] channel in the NO/sGC/PKGI pathway. Electrical field stimulation (EFS)-induced contractions of corpus cavernosum smooth muscle strips were significantly enhanced in the absence of [BK.sub.Ca] channel function. In strips precontracted with phenylephrine, EFS-induced relaxations were converted to contractions by inhibition of sGC, and this was further enhanced by loss of BK channel function. Sildenafil-induced relaxations were decreased to a similar extent by inhibition of sGC or [BK.sub.Ca] channels. At concentrations > 1 [micro]M, sildenafil caused relaxations independent of inhibition of sGC or [BK.sub.Ca] channels. Sildenafil did not affect the enhanced force oscillations that were induced by the loss of [BK.sub.Ca] channel function. Yet, these oscillations could be completely eliminated by blocking L-type voltage-dependent [Ca.sup.2+] channels (VDCCs). These results suggest that therapeutically relevant concentrations of sildenafil act through cGMP and [BK.sub.Ca] channels, and loss of [BK.sub.Ca] channel function leads to hypercontractility, which depends on VDCCs and cannot be modified by the cGMP pathway. smooth muscle; calcium-activated potassium channel; mouse

In the urinary bladder, contractions of the detrusor muscle and urine voiding are induced by the neurotransmitters ACh and ATP, released from parasympathetic nerves. Activation of [K.sup.+] channels, in particular the large-conductance [Ca.sup.2+]-activated [K.sup.+] (BK) channels, opposes increases in excitability and contractility of urinary bladder smooth muscle (UBSM). We have shown that deleting the gene mSlol in mice ([Slo.sup.-/-]), encoding the BK channel, leads to enhanced nerve-mediated and neurotransmitter-dependent contractility of UBSM (38). Here, we examine the location of the BK channel in urinary bladder strips from mouse. Immunohistochemical analysis revealed that the channel is expressed in UBSM but not in nerves that innervate the smooth muscle. The relationship between electrical field stimulation and force generation of the cholinergic and purinergic pathways was examined by applying blockers of the respective receptors in UBSM strips from wild-type and from [Slo.sup.-/-] (knockout) mice. In wild-type strips, the stimulation frequency required to obtain a half-maximal force was significantly lower for the purinergic (7.2 [+ or -] 0.3 Hz) than the cholinergic pathway (19.1 [+ or -] 1.5 Hz), whereas the maximum force was similar. Blocking BK channels with iberiotoxin or ablation of the Slo gene increased cholinergic- and purinergic-mediated force at low frequencies, i.e., significantly decreased the frequency for a half-maximal force. Our results indicate that the BK channel has a very significant role in reducing both cholinergic- and purinergic-induced contractility and suggest that alterations in BK channel expression or function could contribute to pathologies such as overactive detrusor. urinary bladder; neurotransmitter; potassium channel; incontinence; overactive detrusor

Background: KCNMA1‐linked channelopathy is a rare movement disorder first reported in 2005. Paroxysmal non‐kinesigenic dyskinesia (PNKD) in KCNMA1‐linked channelopathy is the most common symptom in patients harboring the KCNMA1‐N999S mutation. PNKD episodes occur up to hundreds of times daily with significant morbidity and limited treatment options, often in the context of epilepsy. Cases: We report 6 cases with the KCNMA1‐N999S variant treated with lisdexamfetamine (0.7–1.25 mg/kg/day), a pro‐drug of dextroamphetamine. Data were collected retrospectively from interviews and chart review. Parent‐reported daily PNKD episode counts were reduced under treatment, ranging from a 10‐fold decrease to complete resolution. Conclusion: Our findings suggest that lisdexamfetamine is an effective therapy for PNKD3 (KCNMA1‐associated PNKD). Treatment produced dramatic reductions in debilitating dyskinesia episodes, without provocation or exacerbation of other KCNMA1‐associated symptoms such as seizures. [ABSTRACT FROM AUTHOR]

The gene expression of atrial natriuretic peptide (ANP) hormone is greatly increased in the left ventricle of the heart of the rat during cardiac hypertrophy. The circulation of the ANP levels in the senescent rat is largely increased by the endocrine release of the left ventricle. The age-associated increase in the ANP gene expression and the cardiac hypertrophy is regulated by a common mechanism and this fact is supported by the correlation between immunoreactive ANP and hypertrophy in the left ventricle of the older rats.

Daily regulation of Ca2+ – 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 Ca2+ channels in a circadian manner. Daytime BK current predominantly requires Ca2+ influx through L-type Ca2+ channels (LTCCs), a time when BK channels are closely coupled with their Ca2+ source. Here we show that daytime BK current is resistant to the Ca2+ chelator BAPTA. However, at night when LTCCs contribute little to BK activation, BK current decreases by a third in BAPTA compared to control EGTA conditions. In phase with this time-of-day specific effect on BK current activation, LTCC current is larger during the day. The specific Ca2+ channel subtypes underlying the LTCC current in SCN, as well as the subtypes contributing the Ca2+ influx relevant for BK current activation, have not been identified. SCN neurons express two LTCC subtypes, CaV1.2 and CaV1.3. While a role for CaV1.2 channels has been identified during the night, CaV1.3 channel modulation has also been suggested to contribute to daytime SCN action potential activity, as well as subthreshold Ca2+ oscillations. Here we characterize the role of CaV1.3 channels in LTCC and BK current activation in SCN neurons using a global deletion of CACNA1D in mouse (CaV1.3 KO). CaV1.3 KO SCN neurons had a 50% reduction in the daytime LTCC current, but not total Ca2+ current, with no difference in Ca2+ current levels at night. During the day, CaV1.3 KO neurons exhibited oscillations in membrane potential, and most neurons, although not all, also had BK currents. Changes in BK current activation were only detectable at the highest voltage tested. These data show that while CaV1.3 channels contribute to the daytime Ca2+ current, this does not translate into a major effect on the daytime BK current. These data suggest that BK current activation does not absolutely require CaV1.3 channels and may therefore also depend on other LTCC subtypes, such as CaV1.2. [ABSTRACT FROM AUTHOR]

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 largeconductance Ca2þ- and voltage-activated Kþ (BK) and L-type Ca2þ 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). However, the contribution of these Ca2þ channels to BK channel activation during action potential firing has not been thoroughly investigated. In this study, we used a pharmacological approach to determine that both LTCCs and RyRs contribute to the baseline membrane potential of SCN action potential waveforms, as well as action potential-evoked BK current, during the day and night, respectively. Since the baseline membrane potential is a major determinant of circadian firing rate, we focused on the LTCCs contributing to low voltage activation of BK channels during the subthreshold phase. For these experiments, two LTCC subtypes found in SCN (CaV1.2 and CaV1.3) were coexpressed with BK channels in heterologous cells, where their differential contributions could be separately measured. CaV1.3 channels produced currents that were shifted to more hyperpolarized potentials compared with CaV1.2, resulting in increased subthreshold Ca2þ and BK currents during an action potential command. These results show that although multiple Ca2þ sources in SCN can contribute to the activation of BK current during an action potential, specific BK-CaV1.3 partnerships may optimize the subthreshold BK current activation that is critical for firing rate regulation. [ABSTRACT FROM AUTHOR]