Residues and Mechanisms for Slow Activation and Ba2+Block of the Cardiac Muscarinic K+ Channel, Kir3.1/Kir3.4

Lancaster, Matthew K.; Dibb, Katharine M.; Quinn, Claire C.; Leach, Robert; Lee, Jong-Kook; Findlay, John B. C.; Boyett, Mark R.

doi:10.1074/jbc.m006565200

Cited by 28 publications

(30 citation statements)

References 36 publications

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“…Mg 2ϩ is known to block instantaneously, whereas polyamine block exhibits slow voltage-dependent blocking and unblocking kinetics (13,27,28). In whole cell patch clamp experiments the polyamine block is found to be responsible for the slow inactivation/activation of GIRK currents measured resulting from voltage steps (28). Our investigation of polyamine block revealed no striking alteration of the blocking/ unblocking time constants in the presence of G␤␥ over-expression.…”

Section: The Physiological Role Of Weakened Inward Rectification-mentioning

confidence: 71%

“…Therefore, changing the inward rectification in the observed way may be related to polyamine and/or Mg 2ϩ -binding properties to the channel. Mg 2ϩ is known to block instantaneously, whereas polyamine block exhibits slow voltage-dependent blocking and unblocking kinetics (13,27,28). In whole cell patch clamp experiments the polyamine block is found to be responsible for the slow inactivation/activation of GIRK currents measured resulting from voltage steps (28).…”

Section: The Physiological Role Of Weakened Inward Rectification-mentioning

confidence: 99%

“…Studies using crystal structures of the bacterial KcsA channel complexed with Ba 2ϩ have located a single Ba 2ϩ -binding site on the cytosolic side of the selectivity filter (29,30). In close proximity to this site are some of the residues that have been implicated to be critical for strong inward rectification (11,28). To test if G␤␥ mediates a conformational change of the GIRK channel that causes weakening of inward rectification by altering structures close to the selectivity filter, we questioned whether or not GIRK channel block by Ba 2ϩ was affected by G␤␥.…”

Section: Affinity For Ba 2ϩ Block Was Reduced Under Weak Inward Rectimentioning

confidence: 99%

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Regulation of the Inward Rectifying Properties of G-protein-activated Inwardly Rectifying K+ (GIRK) Channels by Gβγ Subunits

Hommers

Lohse

Bünemann

2003

Journal of Biological Chemistry

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G␤␥ subunits are known to bind to and activate Gprotein-activated inwardly rectifying K ؉ channels (GIRK) by regulating their open probability and bursting behavior. Studying G-protein regulation of either native GIRK (I KACh ) channels in feline atrial myocytes or heterologously expressed GIRK1/4 channels in Chinese hamster ovary cells and HEK 293 cells uncovered a novel G␤␥ subunit mediated regulation of the inwardly rectifying properties of these channels. I KACh activated by submaximal concentrations of acetylcholine exhibited a ϳ2.5-fold stronger inward rectification than I KACh activated by saturating concentrations of acetylcholine. Similarly, the inward rectification of currents through GIRK1/4 channels expressed in HEK cells was substantially weakened upon maximal stimulation with co-expressed G␤␥ subunits. Analysis of the outward current block underlying inward rectification demonstrated that the fraction of instantaneously blocked channels was reduced when G␤␥ was over-expressed. The G␤␥ induced weakening of inward rectification was associated with reduced potencies for Ba 2؉ and Cs ؉ to block channels from the extracellular side. Based on these results we propose that saturation of the channel with G␤␥ leads to a conformational change within the pore of the channel that reduced the potency of extracellular cations to block the pore and increased the fraction of channels inert to a pore block in outward direction.G-protein-activated inwardly rectifying K ϩ channels (GIRKs) 1 are expressed in many areas of the brain and in supraventricular myocytes of the heart (1, 2). Activation of G-protein-coupled receptors that couple to G i -proteins such as the M 2 muscarinic acetylcholine receptors (M 2 -mAChRs) lead to a dissociation of heterotrimeric G-proteins into activated ␣ subunits and ␤␥ dimers. G␤␥ subunits are known to bind to GIRK channels and increase the open probability of these channels (3, 4). Cardiac I KACh channels are formed by heteromultimers of GIRK1 and GIRK4 subunits (4). The binding site of G␤␥ subunits to GIRK channels was mapped primarily to the C terminus of GIRK1 and GIRK4 (4 -8). Cross-linking studies have demonstrated that the heterotetrameric channel can bind up to 4 G␤␥ subunits (9). However, despite much experimental effort the mechanism by which G␤␥ activates these channels is not well understood.GIRK channels belong to the family of strong inwardly rectifying K ϩ channels, which are characterized by their strong inwardly rectifying current-voltage relationships. The inward rectification has been linked to the presence of intracellular Mg 2ϩ and polyamines (10 -12). These positively charged cytoplasmic ions are thought to block outward K ϩ currents by blocking the pore of channels from the inside (10 -13); however, for a related inwardly rectifying channel Kir2.1 this hypothesis has recently been questioned (14). Inward rectification of K ϩ channels is not only voltage-dependent but also dependent on the extracellular K ϩ concentration (11). The inward rectification of these K ...

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Section: The Physiological Role Of Weakened Inward Rectification-mentioning

confidence: 71%

Section: The Physiological Role Of Weakened Inward Rectification-mentioning

confidence: 99%

Section: Affinity For Ba 2ϩ Block Was Reduced Under Weak Inward Rectimentioning

confidence: 99%

See 1 more Smart Citation

Regulation of the Inward Rectifying Properties of G-protein-activated Inwardly Rectifying K+ (GIRK) Channels by Gβγ Subunits

Hommers

Lohse

Bünemann

2003

Journal of Biological Chemistry

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“…A negatively charged aspartate residue in the second transmembrane domain of the Kir3.1 subunit was identified as the major structural determinant (19). Neutralization of this residue, as in the Kir3.4 subunit, leads to a largely instantaneous onset of current.…”

Section: Muscarinic Control Of Chronotropy Changes During Embryonic Dmentioning

confidence: 99%

Differential subunit composition of the G protein–activated inward-rectifier potassium channel during cardiac development

Fleischmann¹,

Duan²,

Fan³

et al. 2004

J. Clin. Invest.

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“…In the Kir1.1 channel, a weak inward rectifier, introducing a glutamic acid at the counterpart of Glu-224 failed to reproduce the inward rectification observed in Kir2.1 channel (12). Mutation of the residue equivalent to Glu-224 in Kir3.4, a member of another Kir subfamily, also had functional consequence dissimilar to that in Kir2.1 channels (15). These observations, together with the high functional diversity of the cytoplasmic region, raise the question of whether all Kir channels share a vestibule structure similar to that of Kir2.1 channels.…”

mentioning

confidence: 99%

Cytoplasmic Vestibule of the Weak Inward Rectifier Kir6.2 Potassium Channel

Cui

Wang

Fan

2002

Journal of Biological Chemistry

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Residues and Mechanisms for Slow Activation and Ba2+Block of the Cardiac Muscarinic K+ Channel, Kir3.1/Kir3.4

Cited by 28 publications

References 36 publications

Regulation of the Inward Rectifying Properties of G-protein-activated Inwardly Rectifying K+ (GIRK) Channels by Gβγ Subunits

Regulation of the Inward Rectifying Properties of G-protein-activated Inwardly Rectifying K+ (GIRK) Channels by Gβγ Subunits

Differential subunit composition of the G protein–activated inward-rectifier potassium channel during cardiac development

Cytoplasmic Vestibule of the Weak Inward Rectifier Kir6.2 Potassium Channel

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