The role of small-conductance Ca2+-activated K+ channels in the modulation of 4-aminopyridine-induced burst firing in rat cerebellar Purkinje cells

Haghdoost-Yazdi, Hashem; Janahmadi, Mahyar; Behzadi, Gila

doi:10.1016/j.brainres.2007.04.031

Cited by 25 publications

(13 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A subsequent application of 100 nM apamin (+Apa) to both experimental groups completely blocked the AHP currents. a slowly decaying plateau potential (Figure S2A, bottom traces); these results are consistent with previous reports (Cueni et al, 2008;Yazdi et al, 2007). When compared at the midpoint of the response, the plateau potential was significantly more negative in Ca V 2.3 À/À neurons (À44.23 ± 1.65 mV, n = 9) than that in wild-type neurons (À34.23 ± 2.01 mV, n = 5; p = 0.002), suggesting a contribution of Ca V 2.3 channels to this membrane depolarization.…”

Section: Ca V 23 Channels Enhance the Tonic Firing Activity Of Rt Neuronssupporting

confidence: 93%

CaV2.3 Channels Are Critical for Oscillatory Burst Discharges in the Reticular Thalamus and Absence Epilepsy

Zaman

Lee

Park

et al. 2011

Neuron

View full text Add to dashboard Cite

Neurons of the reticular thalamus (RT) display oscillatory burst discharges that are believed to be critical for thalamocortical network oscillations related to absence epilepsy. Ca²+-dependent mechanisms underlie such oscillatory discharges. However, involvement of high-voltage activated (HVA) Ca²+ channels in this process has been discounted. We examined this issue closely using mice deficient for the HVA Ca(v)2.3 channels. In brain slices of Ca(v)2.3⁻/⁻, a hyperpolarizing current injection initiated a low-threshold burst of spikes in RT neurons; however, subsequent oscillatory burst discharges were severely suppressed, with a significantly reduced slow afterhyperpolarization (AHP). Consequently, the lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to γ-butyrolactone-induced absence epilepsy. Local blockade of Ca(v)2.3 channels in the RT mimicked the results of Ca(v)2.3⁻/⁻ mice. These results provide strong evidence that Ca(v)2.3 channels are critical for oscillatory burst discharges in RT neurons and for the expression of absence epilepsy.

show abstract

Section: Ca V 23 Channels Enhance the Tonic Firing Activity Of Rt Neuronssupporting

confidence: 93%

CaV2.3 Channels Are Critical for Oscillatory Burst Discharges in the Reticular Thalamus and Absence Epilepsy

Zaman

Lee

Park

et al. 2011

Neuron

View full text Add to dashboard Cite

show abstract

“…Purkinje cells (PCs) are known to express large conductance (BK) [1–10] and small conductance (SK) [6, 11–14] Ca 2+ -activated K + (K Ca ) channels on their dendrites. K Ca channels together with voltage-gated Ca 2+ channels significantly control the dendritic excitability [6, 15].…”

Section: Introductionmentioning

confidence: 99%

Controlling Ca2+-Activated K+ Channels with Models of Ca2+ Buffering in Purkinje Cells

2010

View full text Add to dashboard Cite

Intracellular Ca2+ concentrations play a crucial role in the physiological interaction between Ca2+ channels and Ca2+-activated K+ channels. The commonly used model, a Ca2+ pool with a short relaxation time, fails to simulate interactions occurring at multiple time scales. On the other hand, detailed computational models including various Ca2+ buffers and pumps can result in large computational cost due to radial diffusion in large compartments, which may be undesirable when simulating morphologically detailed Purkinje cell models. We present a method using a compensating mechanism to replace radial diffusion and compared the dynamics of different Ca2+ buffering models during generation of a dendritic Ca2+ spike in a single compartment model of a PC dendritic segment with Ca2+ channels of P- and T-type and Ca2+-activated K+ channels of BK- and SK-type. The Ca2+ dynamics models used are (1) a single Ca2+ pool; (2) two Ca2+ pools, respectively, for the fast and slow transients; (3) detailed Ca2+ dynamics with buffers, pump, and diffusion; and (4) detailed Ca2+ dynamics with buffers, pump, and diffusion compensation. Our results show that detailed Ca2+ dynamics models have significantly better control over Ca2+-activated K+ channels and lead to physiologically more realistic simulations of Ca2+ spikes and bursting. Furthermore, the compensating mechanism largely eliminates the effect of removing diffusion from the model on Ca2+ dynamics over multiple time scales.Electronic supplementary materialThe online version of this article (doi:10.1007/s12311-010-0224-3) contains supplementary material, which is available to authorized users.

show abstract

“…The association of this series with antimalarial activity was subsequently also noted in the published GlaxoSmithKline Tres Cantos antimalarial set [34]. More commonly, aminopyridines are known for kinase inhibition [101,102], as GPCR antagonists [103] and as ion channel modulators [35].…”

Section: 5-diaryl-2-aminopyridines As Antimalarialsmentioning

confidence: 96%

Antimalarial Aminothiazoles and Aminopyridines From Phenotypic Whole-Cell Screening Of A SoftFocus ^® Library

Paquet

Gordon²,

Waterson

et al. 2012

Future Med. Chem.

View full text Add to dashboard Cite

The current state of antimalarial drug resistance emphasizes the need for new therapies with novel modes of action that will add a significant benefit compared with current standards. In this regard, high throughput phenotypic whole-cell screening aids the discovery of novel antiplasmodial scaffolds that are inherently suited to hit-to-lead and lead-optimization efforts. The aminothiazoles and aminopyridines exemplify two such compound classes stemming from whole-cell screening. Respective structure-activity relationship determinations and subsequent optimization around these scaffolds led to frontrunner compounds in each series, which possess the desired antimalarial efficacy, bioavailability and metabolic stability to further progress medicinal chemistry programs.

show abstract

The role of small-conductance Ca2+-activated K+ channels in the modulation of 4-aminopyridine-induced burst firing in rat cerebellar Purkinje cells

Cited by 25 publications

References 29 publications

CaV2.3 Channels Are Critical for Oscillatory Burst Discharges in the Reticular Thalamus and Absence Epilepsy

CaV2.3 Channels Are Critical for Oscillatory Burst Discharges in the Reticular Thalamus and Absence Epilepsy

Controlling Ca2+-Activated K+ Channels with Models of Ca2+ Buffering in Purkinje Cells

Antimalarial Aminothiazoles and Aminopyridines From Phenotypic Whole-Cell Screening Of A SoftFocus ^® Library

Contact Info

Product

Resources

About

The role of small-conductance Ca2+-activated K+ channels in the modulation of 4-aminopyridine-induced burst firing in rat cerebellar Purkinje cells

Cited by 25 publications

References 29 publications

CaV2.3 Channels Are Critical for Oscillatory Burst Discharges in the Reticular Thalamus and Absence Epilepsy

CaV2.3 Channels Are Critical for Oscillatory Burst Discharges in the Reticular Thalamus and Absence Epilepsy

Controlling Ca2+-Activated K+ Channels with Models of Ca2+ Buffering in Purkinje Cells

Antimalarial Aminothiazoles and Aminopyridines From Phenotypic Whole-Cell Screening Of A SoftFocus ® Library

Contact Info

Product

Resources

About

Antimalarial Aminothiazoles and Aminopyridines From Phenotypic Whole-Cell Screening Of A SoftFocus ^® Library