Pharmacology of A-Type K+ Channels

Johnston, Jamie

doi:10.1007/164_2021_456

Cited by 5 publications

(2 citation statements)

References 87 publications

(103 reference statements)

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“…3c and Table 2). That is, the Va 1/2 of A-type voltage-gated K + currents in type III cells was 17.9 ± 4.5 mV (n = 17), which bears resemblance to the Va 1/2 of Kv3.3 and Kv3.4 channels at ~ 7 and 13-19 mV, respectively, which are more depolarized values as compared to the other A-type K + channels (Coetzee et al 1999;Fernandez et al 2003;Johnston 2021). Therefore, it suggests that type III cells express high voltage-activated A-type K + channels.…”

Section: Voltage Dependency Of Activation and Steady-state Inactivationmentioning

confidence: 74%

Characteristics of A-type voltage-gated K+ currents expressed on sour-sensing type III taste receptor cells in mice

Moribayashi,

Nakao,

Ohtubo

2024

Cell Tissue Res

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Sour taste is detected by type III taste receptor cells that generate membrane depolarization with action potentials in response to HCl applied to the apical membranes. The shape of action potentials in type III cells exhibits larger afterhyperpolarization due to activation of transient A-type voltage-gated K+ currents. Although action potentials play an important role in neurotransmitter release, the electrophysiological features of A-type K+ currents in taste buds remain unclear. Here, we examined the electrophysiological properties of A-type K+ currents in mouse fungiform taste bud cells using in-situ whole-cell patch clamping. Type III cells were identified with SNAP-25 immunoreactivity and/or electrophysiological features of voltage-gated currents. Type III cells expressed A-type K+ currents which were completely inhibited by 10 mM TEA, whereas IP3R3-immunoreactive type II cells did not. The half-maximal activation and steady-state inactivation of A-type K+ currents were 17.9 ± 4.5 (n = 17) and − 11.0 ± 5.7 (n = 17) mV, respectively, which are similar to the features of Kv3.3 and Kv3.4 channels (transient and high voltage-activated K+ channels). The recovery from inactivation was well fitted with a double exponential equation; the fast and slow time constants were 6.4 ± 0.6 ms and 0.76 ± 0.26 s (n = 6), respectively. RT-PCR experiments suggest that Kv3.3 and Kv3.4 mRNAs were detected at the taste bud level, but not at single-cell levels. As the phosphorylation of Kv3.3 and Kv3.4 channels generally leads to the modulation of cell excitability, neuromodulator-mediated A-type K+ channel phosphorylation likely affects the signal transduction of taste.

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Section: Voltage Dependency Of Activation and Steady-state Inactivationmentioning

confidence: 74%

Characteristics of A-type voltage-gated K+ currents expressed on sour-sensing type III taste receptor cells in mice

Moribayashi,

Nakao,

Ohtubo

2024

Cell Tissue Res

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“…The molecular basis of this functional diversity resides in 40 Kv channel genes classi ed in 12 sub-families and many additional genes encoding ancillary beta subunits, which are differentially expressed in relevant tissues and parts of the brain and different subcellular compartments [3][4][5][6] . This diversity has stimulated a special interest in developing small-molecules and peptides that could selectively modulate aspects of function in excitable tissues and, therefore, could have potential as novel medicinal agents [7][8][9][10][11][12] . The search for Kv channel openers or positive allosteric modulators (PAMs) has gained most of the attention because they could help treat common hyperexcitability disorders (epilepsy, neuropathic pain, tinnitus, cardiac arrhythmias, etc.)…”

Section: Introductionmentioning

confidence: 99%

The unique turret region of Kv3 channels governs the mechanism of action of highly specific positive allosteric modulators.

Covarrubias

Liang

et al. 2023

Preprint

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Small-molecule modulators of diverse voltage-gated K+ (Kv) channels may help treat severe neurological disorders. However, the development of selective modulators requires an understanding of their mechanism-of-action (MoA). We applied an orthogonal approach to elucidate the MoA of an imidazolidinedione derivative (AUT5), which is a highly specific positive allosteric modulator (PAM) of Kv3.1 and Kv3.2 channels. AUT5 modulation involves positive cooperativity and preferential stabilization of the open state. Critically, we found that the unique and highly conserved extracellular turret region of Kv3.1 and Kv3.2 essentially governs AUT5 modulation. Furthermore, leveraging on the cryo-EM structure of Kv3.1a, atomistic blind docking calculations revealed four equivalent AUT5 binding sites near the turrets and between the voltage-sensing and pore domains of the channel’s tetrameric assembly. Therefore, the unique Kv3 turret emerges as a novel structural correlate of the selective MoA of a new class of Kv3 channel PAMs with a therapeutic potential.

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Therapeutic Targeting of Potassium Channels

Gamper,

Huang,

et al. 2024

Ion Channels as Targets in Drug Discovery

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Pharmacology of A-Type K+ Channels

Cited by 5 publications

References 87 publications

Characteristics of A-type voltage-gated K+ currents expressed on sour-sensing type III taste receptor cells in mice

Characteristics of A-type voltage-gated K+ currents expressed on sour-sensing type III taste receptor cells in mice

The unique turret region of Kv3 channels governs the mechanism of action of highly specific positive allosteric modulators.

Therapeutic Targeting of Potassium Channels

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