Emerging complexities of lipid regulation of potassium channels

Kurata, Harley T.

doi:10.1085/jgp.201611671

Cited by 2 publications

(2 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This phenomenon originates in a voltage-dependent block by intracellular Mg 2+ and polyamines preventing excessive K + efflux 1 . K ir channels form homo- as well as heterotetramers, which are generally activated by phosphatidylinositol 4,5-bisphosphate (PIP 2 ) 2 . Members of the K ir 3 (GIRK) channel subfamily are additionally regulated by intracellular sodium and the βγ subunits of the G-proteins, Gβγ (an obligatory dimer of Gβ and Gγ) 3 .…”

Section: Introductionmentioning

confidence: 99%

A selectivity filter mutation provides insights into gating regulation of a K+ channel

et al. 2022

View full text Add to dashboard Cite

G-protein coupled inwardly rectifying potassium (GIRK) channels are key players in inhibitory neurotransmission in heart and brain. We conducted molecular dynamics simulations to investigate the effect of a selectivity filter (SF) mutation, G154S, on GIRK2 structure and function. We observe mutation-induced loss of selectivity, changes in ion occupancy and altered filter geometry. Unexpectedly, we reveal aberrant SF dynamics in the mutant to be correlated with motions in the binding site of the channel activator Gβγ. This coupling is corroborated by electrophysiological experiments, revealing that GIRK2wt activation by Gβγ reduces the affinity of Ba2+ block. We further present a functional characterization of the human GIRK2G154S mutant validating our computational findings. This study identifies an allosteric connection between the SF and a crucial activator binding site. This allosteric gating mechanism may also apply to other potassium channels that are modulated by accessory proteins.

show abstract

Section: Introductionmentioning

confidence: 99%

A selectivity filter mutation provides insights into gating regulation of a K+ channel

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The potassium inward rectifier K + (Kir) channel induces the difference in intracellular and extracellular potassium concentration and cell membrane hyperpolarization due to the change of membrane potential, which maintains the resting potential and regulates cell excitability by reducing the amplitude and frequency of action potential. As a member of Kir family, G protein-gated inwardly rectifying K + (GIRK) channels form homo-or heterotetramers and have been reported to be activated by the intracellular phosphatidylinositol 4,5-diphosphate (PIP2) 1 , the Na + and/or the Gβγ subunits (an essential dimer of Gβ and Gγ) of G proteins 2 . Considering the key role of GIRK channels in many neurological processes, such as drug addiction, arrhythmias, and several neurological disorders, the necessity of developing effective and specific modulators has been generally admitted in view of medical potential 3 .…”

Section: Introductionmentioning

confidence: 99%

Insights into the outward K+ currents-based gating mechanism of GIRK2 channel

Wang

Lü

2023

Biophysical Society of GuangDong Province Academic Forum: Precise Photons and Life Health (PPLH 2022)

View full text Add to dashboard Cite

GIRK channels have been involved in numerous physiological functions by regulating cellular excitability. Considering the characteristics of inward rectification, structure activity relationships of GIRK channels have been studied extensively based on the inward movements of ions. In contrast, the outward K + currents based gating mechanism remains to be investigated in depth, although some drug molecules (dofetilide, cromakalim, and pinacidil etc.) exert medical effects by the current block or activation. In this study, the all-atom microsecond-scale molecular dynamics method was employed to explore the outward currents based gating mechanism of the GRK2 channels, which were modulated by different factors (Na + , G, and Na + -G). The results show that the Na + and G subunits work together to activate the GIRK2 channel, in which Na + predominantly regulates the G-loop gate, while G subunits mainly regulate the HBC gate. Our findings provide structural insights into the gating mechanism of GIRK channels and help to understand the pathology and pharmacodynamics mechanisms of drugs related to outflow currents.

show abstract

Emerging complexities of lipid regulation of potassium channels

Cited by 2 publications

References 22 publications

A selectivity filter mutation provides insights into gating regulation of a K+ channel

A selectivity filter mutation provides insights into gating regulation of a K+ channel

Insights into the outward K+ currents-based gating mechanism of GIRK2 channel

Contact Info

Product

Resources

About