New Insights on KCa3.1 Channel Modulation

2020 ◽  
Vol 26 (18) ◽  
pp. 2096-2101
Author(s):  
Giuseppe Manfroni ◽  
Francesco Ragonese ◽  
Lorenzo Monarca ◽  
Andrea Astolfi ◽  
Loretta Mancinelli ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Critical Role ◽  
Calcium Signalling ◽  
Typical Feature ◽  
Open Probability ◽  
Pharmacological Agents ◽  
Channel Modulation ◽  
Calcium Dependent ◽  
Modelling Techniques ◽  
Calcium Activated Potassium Channel

The human intermediate conductance calcium-activated potassium channel, KCa3.1, is involved in several pathophysiological conditions playing a critical role in cell secretory machinery and calcium signalling. The recent cryo-EM analysis provides new insights for understanding the modulation by both endogenous and pharmacological agents. A typical feature of this channel is the low open probability in saturating calcium concentrations and its modulation by potassium channel openers (KCOs), such as benzo imidazolone 1-EBIO, without changing calcium-dependent activation. In this paper, we proposed a model of KCOs action in the modulation of channel activity. The KCa3.1 channel has a very rich pharmacological profile with several classes of molecules that selectively interact with different binding sites of the channel. Among them, benzo imidazolones can be openers (positive modulators such as 1-EBIO, DC-EBIO) or blockers (negative modulators such as NS1619). Through computation modelling techniques, we identified the 1,4-benzothiazin-3-one as a promising scaffold to develop new KCa3.1 channel modulators. Further studies are needed to explore the potential use of 1-4 benzothiazine- 3-one in KCa3.1 modulation and its pharmacological application.

Characterization of Gating and Peptide Block of mSlo, a Cloned Calcium-Dependent Potassium Channel

1997 ◽  
Vol 78 (6) ◽  
pp. 2937-2950 ◽  
Author(s):  
Deirdre A. Sullivan ◽  
Mats H. Holmqvist ◽  
Irwin B. Levitan
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Potassium Channel ◽  
Critical Role ◽  
Single Amino Acid ◽  
Significant Shift ◽  
Triple Mutant ◽  
Calcium Dependent ◽  
Loop Region

Sullivan, Deirdre A., Mats H. Holmqvist, and Irwin B. Levitan. Characterization of gating and peptide block of mSlo, a cloned calcium-dependent potassium channel. J. Neurophysiol. 78: 2937–2950, 1997. The 20 amino acid Shaker inactivation peptide blocks mSlo, a cloned calcium-dependent potassium channel. Changing the charge and degree of hydrophobicity of the peptide alters its blocking kinetics. A “triple mutant” mSlo channel was constructed in which three amino acids (T256, S259, and L262), equivalent to those identified as part of the peptide's receptor site in the S4–S5 cytoplasmic loop region of the Shaker channel, were mutated simultaneously to alanines. These mutations produce only limited changes in the channel's susceptibility to block by a series of peptides of varying charge and hydrophobicity but do alter channel gating. The triple mutant channel shows a significant shift in its calcium-activation curve as compared with the wild-type channel. Analysis of the corresponding single amino acid mutations shows that mutation at position L262 causes the most dramatic change in mSlo gating. These results suggest that the three amino acids mutated in the mSlo S4–S5 loop may contribute to, but are not essential for, peptide binding. On the other hand, they do play a critical role in the channel's calcium-sensing mechanism.

A calcium-activated potassium channel causes frequency-dependent action-potential failures in a mammalian nerve terminal

1993 ◽  
Vol 70 (1) ◽  
pp. 284-298 ◽  
Author(s):  
K. Bielefeldt ◽  
M. B. Jackson
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Potassium Channel ◽  
Action Potentials ◽  
Calcium Concentration ◽  
Calcium Influx ◽  
Calcium Dependent ◽  
Potential Failure ◽  
Bayk 8644 ◽  
Calcium Activated Potassium Channel

1. The contribution of a calcium-activated potassium channel to action-potential failure was studied in nerve terminals of the rat posterior pituitary. 2. Depolarizing current injections under current clamp were faithfully followed by action potentials for stimulation frequencies of < or = 12 Hz. Further increases in frequency resulted in action-potential failure within a few hundred milliseconds. The fraction of failures increased with stimulation frequency. This decrease in excitability was concomitant with a hyperpolarization from -57.3 +/- 1.4 to -61.3 +/- 1.4 (SE) mV. 3. The decrease in excitability was dependent on calcium influx through voltage-dependent calcium channels, because action-potential failures did not occur at frequencies < or = 30 Hz in the presence of cadmium. The dihydropyridine agonist BayK 8644 increased the fraction of failed action potentials. 4. Depolarizations from -80 to 10 mV for 3 s evoked macroscopic potassium currents with a rapidly activated, transient component and a slowly developing, noninactivating component. The late outward current was dependent on calcium influx, because it was reduced by cadmium and enhanced by BayK 8644. 5. Tetraethylammonium and 4-aminopyridine effectively blocked potassium outward currents but failed to distinguish this calcium-dependent potassium channel from the other two potassium channels in this preparation. Charybdotoxin and apamin did not affect potassium currents in this preparation. 6. In excised inside-out patches, the calcium-dependent potassium channel had a slope conductance of 193 pS. The open probability changed e-fold per 14.8 mV change in membrane potential with a calcium concentration at the cytoplasmic membrane face ([Ca]i) of 100 nM. 7. The channel was highly sensitive to [Ca]i. Depolarizations to 100 mV at 10 nM [Ca]i activated the channel half-maximally. When [Ca]i was raised to 250 nM, the voltage for half-maximal activation shifted to -16 mV. Calcium also decreased the steepness of the voltage activation curve. 8. At a constant membrane potential, pressure ejection of calcium to the cytosolic face of an excised patch activated the channel with a delay of 82 ms. This slow activation in excised patches was consistent with the slow activation of the delayed component of the macroscopic current. 9. At constant calcium concentration, the time course of activation exhibited a strong voltage dependence. Most of the channels did not inactivate during depolarizations lasting < or = 300 ms. 10. The channel exhibited complex gating, with at least two distinct open and closed states.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals A well-known potassium channel plays a critical role in lysosomes

2017 ◽  
Vol 216 (6) ◽  
pp. 1513-1515 ◽  
Author(s):  
Michael X. Zhu
Keyword(s):  
Membrane Potential ◽  
Potassium Channel ◽  
Critical Role ◽  
Patch Clamping ◽  
Cell Biol ◽  
New Thinking ◽  
And Function ◽  
Calcium Activated Potassium Channel ◽  
Acidic Organelles ◽  
Lysosome Membrane

Whole-endolysosome patch clamping presents new opportunities to identify and characterize channels pivotal for these acidic organelles. In this issue (Wang et al., 2017. J. Cell Biol. https://doi.org/10.1083/jcb.201612123), the identification of a role for the large conductance calcium-activated potassium channel brings new thinking about regulation of lysosome membrane potential and function.

scholarly journals Calcium-dependent Gating of MthK, a Prokaryotic Potassium Channel

2006 ◽  
Vol 127 (6) ◽  
pp. 673-685 ◽  
Author(s):  
Brittany Zadek ◽  
Crina M. Nimigean
Keyword(s):  
Potassium Channel ◽  
Single Channel ◽  
Hill Coefficient ◽  
Special Focus ◽  
Open Probability ◽  
Calcium Dependent ◽  
Channel Opening ◽  
High Resolution Structure ◽  
Fast Gating ◽  
Inwardly Rectifying

MthK is a calcium-gated, inwardly rectifying, prokaryotic potassium channel. Although little functional information is available for MthK, its high-resolution structure is used as a model for eukaryotic Ca2+-dependent potassium channels. Here we characterize in detail the main gating characteristics of MthK at the single-channel level with special focus on the mechanism of Ca2+ activation. MthK has two distinct gating modes: slow gating affected mainly by Ca2+ and fast gating affected by voltage. Millimolar Ca2+ increases MthK open probability over 100-fold by mainly increasing the frequency of channel opening while leaving the opening durations unchanged. The Ca2+ dose–response curve displays an unusually high Hill coefficient (n = ∼8), suggesting strong coupling between Ca2+ binding and channel opening. Depolarization affects both the fast gate by dramatically reducing the fast flickers, and to a lesser extent, the slow gate, by increasing MthK open probability. We were able to capture the mechanistic features of MthK with a modified MWC model.

Sign in / Sign up

Export Citation Format

Share Document