Subtype‐selective positive modulation of K<sub>Ca</sub>2 channels depends on the HA/HB helices

Nam, Young‐Woo; Cui, Meng; El-Sayed, Naglaa Salem; Orfali, Razan; Nguyen, Martin; Yang, Guangning; Rahman, Mohammad Asikur; Lee, Judy; Zhang, Miao

doi:10.1111/bph.15676

Cited by 10 publications

(21 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our recent study has revealed that the subtype selectivity of CyPPA for K Ca 2.2a and K Ca 2.3 over K Ca 3.1 channels relies on the HA/HB helices. 33 We aligned the amino acid sequences of the rat K Ca 2.2a, human K Ca 2.3, and human K Ca 3.1 channel subtypes in the proximal C terminus ( Figure 2 A). Rat K Ca 2.2a has a valine residue (V420) equivalent to a methionine residue (M311) of the human K Ca 3.1 channel in the HA helix.…”

Section: Resultsmentioning

confidence: 99%

“…The V-to-M and K-to-R discrepancies between the amino acid sequences of rat K Ca 2.2a and human K Ca 3.1 channels provide an explanation for the subtype selectivity of CyPPA. 33 …”

Section: Resultsmentioning

confidence: 99%

“…The V-to-M and K-to-R discrepancies between the amino acid sequences of rat K Ca 2.2a and human K Ca 3.1 channels provide an explanation for the subtype selectivity of CyPPA. 33 We then set out to explore the structural determinants for the ∼21-fold subtype selectivity of compound 4 for human K Ca 2.3 over rat K Ca 2.2 channels. Human K Ca 2.3 has an isoleucine (I568) equivalent to V420 in the HA helix of rat K Ca 2.2a channels (Figure 2A).…”

Section: Subtype Selectivity Of Compoundmentioning

confidence: 99%

“…We recently identified the binding site of a prototype K Ca 2.2a/K Ca 2.3 channel modulator, CyPPA. 33 We have synthesized a new series of CyPPA analogues. 34 Here, we report the identification of a subtype-selective K Ca 2.3 channel modulator, compound 4 , that is ∼21-fold more potent on potentiating human K Ca 2.3 than rat K Ca 2.2a channels.…”

Section: Introductionmentioning

confidence: 99%

“…K Ca 2.3 and K Ca 2.2a channels have similar amino acid sequences in their cytoplasmic gates, which makes it difficult to develop subtype-selective positive modulators discriminating these two subtypes. We recently identified the binding site of a prototype K Ca 2.2a/K Ca 2.3 channel modulator, CyPPA . We have synthesized a new series of CyPPA analogues .…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Subtype-Selective Positive Modulation of K_Ca2.3 Channels Increases Cilia Length

et al. 2022

Self Cite

View full text Add to dashboard Cite

Small-conductance Ca 2+ -activated potassium (K Ca 2.x) channels are gated exclusively by intracellular Ca 2+ . The activation of K Ca 2.3 channels induces hyperpolarization, which augments Ca 2+ signaling in endothelial cells. Cilia are specialized Ca 2+ signaling compartments. Here, we identified compound 4 that potentiates human K Ca 2.3 channels selectively. The subtype selectivity of compound 4 for human K Ca 2.3 over rat K Ca 2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of K Ca 2.3 channels by compound 4 increased flow-induced Ca 2+ signaling and cilia length, while negative modulation by AP14145 reduced flow-induced Ca 2+ signaling and cilia length. These findings were corroborated by the increased cilia length due to the expression of Ca 2+ -hypersensitive K Ca 2.3_G351D mutant channels and the reduced cilia length resulting from the expression of Ca 2+ -hyposensitive K Ca 2.3_I438N channels. Collectively, we were able to associate functions of K Ca 2.3 channels and cilia, two crucial components in the flow-induced Ca 2+ signaling of endothelial cells, with potential implications in vasodilation and ciliopathic hypertension.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The V-to-M and K-to-R discrepancies between the amino acid sequences of rat K Ca 2.2a and human K Ca 3.1 channels provide an explanation for the subtype selectivity of CyPPA. 33 …”

Section: Resultsmentioning

confidence: 99%

Section: Subtype Selectivity Of Compoundmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Subtype-Selective Positive Modulation of K_Ca2.3 Channels Increases Cilia Length

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

K_Ca2.2 (KCNN2): A physiologically and therapeutically important potassium channel

Rahman,

Orfali,

Dave

et al. 2023

J of Neuroscience Research

Self Cite

View full text Add to dashboard Cite

One group of the K+ ion channels, the small‐conductance Ca2+‐activated potassium channels (KCa2.x, also known as SK channels family), is widely expressed in neurons as well as the heart, endothelial cells, etc. They are named small‐conductance Ca2+‐activated potassium channels (SK channels) due to their comparatively low single‐channel conductance of about ~10 pS. These channels are insensitive to changes in membrane potential and are activated solely by rises in the intracellular Ca2+. According to the phylogenic research done on the KCa2.x channels family, there are three channels' subtypes: KCa2.1, KCa2.2, and KCa2.3, which are encoded by KCNN1, KCNN2, and KCNN3 genes, respectively. The KCa2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. KCa2.x channels inhibit excitatory postsynaptic potentials (EPSPs) in neuronal dendrites and contribute to the medium afterhyperpolarization (mAHP) that follows the action potential bursts. Multiple brain regions, including the hippocampus, express the KCa2.2 channel encoded by the KCNN2 gene on chromosome 5. Of particular interest, rat cerebellar Purkinje cells express KCa2.2 channels, which are crucial for various cellular processes during development and maturation. Patients with a loss‐of‐function of KCNN2 mutations typically exhibit extrapyramidal symptoms, cerebellar ataxia, motor and language developmental delays, and intellectual disabilities. Studies have revealed that autosomal dominant neurodevelopmental movement disorders resembling rodent symptoms are caused by heterozygous loss‐of‐function mutations, which are most likely to induce KCNN2 haploinsufficiency. The KCa2.2 channel is a promising drug target for spinocerebellar ataxias (SCAs). SCAs exhibit the dysregulation of firing in cerebellar Purkinje cells which is one of the first signs of pathology. Thus, selective KCa2.2 modulators are promising potential therapeutics for SCAs.

show abstract

Development and validation of an ultrahigh‐performance liquid chromatography–tandem mass spectrometry method to investigate the plasma pharmacokinetics of a K_Ca2.2/K_Ca2.3 positive allosteric modulator in mice

Rahman

Chandrashekar

Nam

et al. 2023

Rapid Comm Mass Spectrometry

Self Cite

View full text Add to dashboard Cite

Rationale There is currently no treatment for spinocerebellar ataxias (SCAs), which are a group of genetic disorders that often cause a lack of coordination, difficulty walking, slurred speech, tremors, and eventually death. Activation of KCa2.2/KCa2.3 channels reportedly exerts beneficial effects in SCAs. Here, we report the development and validation of an analytical method for quantitating a recently developed positive allosteric modulator of KCa2.2/KCa2.3 channels (compound 2q) in mouse plasma. Methods Mouse plasma samples (10 μL) containing various concentrations of 2q were subjected to protein precipitation in the presence of a structurally similar internal standard (IS). Subsequently, the analytes were separated on a C18 ultrahigh‐performance liquid chromatography column and detected by a tandem mass spectrometer. The method was validated using US Food and Drug Administration (FDA) guidelines. Finally, the validated assay was applied to the measurement of the plasma concentrations of 2q in plasma samples taken from mice after single intravenous doses of 2 mg/kg of 2q, and the pharmacokinetic parameters of 2q were determined. Results The calibration standards were linear (r2 ≥ 0.99) in the range of 1.56–200 nM of 2q with intra‐ and inter‐run accuracy and precision values within the FDA guidelines. The lower limit of quantitation of the assay was 1.56 nM (0.258 pg on the column). The recoveries of 2q and IS from plasma were >94%, with no appreciable matrix effect. The assay showed no significant carryover, and the plasma samples stored at −80°C or the processed samples stored in the autosampler at 10°C were stable for at least 3 weeks and 36 h, respectively. After intravenous injection, 2q showed a bi‐exponential decline pattern in the mouse plasma, with a clearance of 30 mL/min/kg, a terminal volume of distribution of 1.93 mL/kg, and a terminal half‐life of 45 min. Conclusions The developed assay is suitable for preclinical pharmacokinetic–pharmacodynamic studies of 2q as a potential drug candidate for ataxias.

show abstract

Subtype‐selective positive modulation of K_Ca2 channels depends on the HA/HB helices

Cited by 10 publications

References 42 publications

Subtype-Selective Positive Modulation of K_Ca2.3 Channels Increases Cilia Length

Subtype-Selective Positive Modulation of K_Ca2.3 Channels Increases Cilia Length

K_Ca2.2 (KCNN2): A physiologically and therapeutically important potassium channel

Development and validation of an ultrahigh‐performance liquid chromatography–tandem mass spectrometry method to investigate the plasma pharmacokinetics of a K_Ca2.2/K_Ca2.3 positive allosteric modulator in mice

Contact Info

Product

Resources

About

Subtype‐selective positive modulation of KCa2 channels depends on the HA/HB helices

Cited by 10 publications

References 42 publications

Subtype-Selective Positive Modulation of KCa2.3 Channels Increases Cilia Length

Subtype-Selective Positive Modulation of KCa2.3 Channels Increases Cilia Length

KCa2.2 (KCNN2): A physiologically and therapeutically important potassium channel

Development and validation of an ultrahigh‐performance liquid chromatography–tandem mass spectrometry method to investigate the plasma pharmacokinetics of a KCa2.2/KCa2.3 positive allosteric modulator in mice

Contact Info

Product

Resources

About

Subtype‐selective positive modulation of K_Ca2 channels depends on the HA/HB helices

Subtype-Selective Positive Modulation of K_Ca2.3 Channels Increases Cilia Length

Subtype-Selective Positive Modulation of K_Ca2.3 Channels Increases Cilia Length

K_Ca2.2 (KCNN2): A physiologically and therapeutically important potassium channel

Development and validation of an ultrahigh‐performance liquid chromatography–tandem mass spectrometry method to investigate the plasma pharmacokinetics of a K_Ca2.2/K_Ca2.3 positive allosteric modulator in mice