Mechanism of PLC-Mediated Kir3 Current Inhibition

Keselman, Inna; Fribourg, Miguel; Felsenfeld, Dan P.; Logothetis, Diomedes E.

doi:10.4161/chan.4321

Cited by 49 publications

(46 citation statements)

References 51 publications

(87 reference statements)

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“…Hydrolysis of PIP 2 has been indeed suggested as a contributing mechanism to the slow time-scale desensitization of K ACh currents in response to ACh in cardiac myocytes and heterologous expression systems. 47,48 The durations of the openings and bursts of Kir channels displayed different sensitivities to PIP 2 levels. Our single-channel studies of Kir3.4*-S176P suggested that the open-time kinetics of appeared to depend on the specific batch of oocytes used, which made a rigorous characterization difficult.…”

Section: Discussionmentioning

confidence: 99%

Stoichiometry of Kir channels with phosphatidylinositol bisphosphate

Jin

Sui²,

Rosenhouse‐Dantsker³

et al. 2008

Channels

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Phosphatidylinositol bisphosphate (PIP 2 ) is the most abundant phosphoinositide in the plasma membrane of cells and its interaction with many ion channel proteins has proven to be a critical factor enabling ion channel gating. All members of the inwardly rectifying potassium (Kir) channel family depend on PIP 2 for their activity, displaying distinct affinities and stereospecificities of interaction with the phosphoinositide. Here, we explored the stoichiometry of Kir channels with PIP 2 . We first showed that PIP 2 regulated the activity of Kir3.4 channels mainly by altering their bursting behavior. Detailed burst analysis indicates that the channels assumed up to four open states and a connectivity of four between open and closed states depending on the available PIP 2 levels. Moreover, by controlling the number of PIP 2 -sensitive subunits in the stoichiometry of a tetrameric Kir2.1 channel, we showed that characteristic channel activity was obtained when at least two wild-type subunits were present. Our studies support a kinetic model for gating of Kir channels by PIP 2 , where each of the four open states corresponds to the channel activated by one to four PIP 2 molecules.

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Section: Discussionmentioning

confidence: 99%

Stoichiometry of Kir channels with phosphatidylinositol bisphosphate

Jin

Sui²,

Rosenhouse‐Dantsker³

et al. 2008

Channels

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“…The net downstream effect of PKC activation on Kir3 channels is current inhibition, allowing for increased cellular excitability (Stevens et al, 1999;Mao et al, 2004;Keselman et al, 2007). Gq-coupled receptor activation also simultaneously depletes the local concentration of PIP 2 by hydrolysis to IP 3 , which decreases Kir3 channel activity because PIP 2 is a required component for activation of Kir3 channels (Huang et al, 1998;Zhang et al, 1999). The combination of PKC activation and PIP 2 depletion acts in concert to further inhibit Kir3 channel activity.…”

Section: Introductionmentioning

confidence: 99%

A Critical Gating Switch at a Modulatory Site in Neuronal Kir3 Channels

Adney

Meng

et al. 2015

J. Neurosci.

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Inwardly rectifying potassium channels enforce tight control of resting membrane potential in excitable cells. The Kir3.2 channel, a member of the Kir3 subfamily of G-protein-activated potassium channels (GIRKs), plays several roles in the nervous system, including key responsibility in the GABA B pathway of inhibition, in pain perception pathways via opioid receptors, and is also involved in alcoholism. PKC phosphorylation acts on the channel to reduce activity, yet the mechanism is incompletely understood. Using the heterologous Xenopus oocyte system combined with molecular dynamics simulations, we show that PKC modulation of channel activity is dependent on Ser-196 in Kir3.2 such that, when this site is phosphorylated, the channel is less sensitive to PKC inhibition. This reduced inhibition is dependent on an interaction between phospho-Ser (

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“…However, others [15,23,32,36] suggest that the downstream activation of PKC underlies the inhibition of I K,ACh . There are also some pieces of evidence to suggest that reduction in membrane PIP 2 and PKC activation are both involved in the I K,ACh inhibition by agonists such as carbachol [22] and ACh [17].…”

Section: Discussionmentioning

confidence: 99%

Regulatory mechanisms underlying the modulation of GIRK1/GIRK4 heteromeric channels by P2Y receptors

Ding

Matsuura

et al. 2012

Pflugers Arch - Eur J Physiol

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The muscarinic K(+) channel (I (K,ACh)) is a heterotetramer composed of GIRK1 (Kir3.1) and GIRK4 (Kir3.4) subunits of a G protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart. I (K,ACh) displays biphasic changes (activation followed by inhibition) through the stimulation of the purinergic P2Y receptors, but the regulatory mechanism involved in these modulation of I (K,ACh) by P2Y receptors remains to be fully elucidated. Various P2Y receptor subtypes and GIRK1/GIRK4 (I (GIRK)) were co-expressed in Chinese hamster ovary cells, and the effect of stimulation of P2Y receptor subtypes on I (GIRK) were examined using the whole-cell patch-clamp method. Extracellular application of 10 μM ATP induced a transient activation of I (GIRK) through the P2Y(1) receptor, which was completely abolished by pretreatment with pertussis toxin. ATP initially caused an additive transient increase in ACh-activated I (GIRK) (via M(2) receptor), which was followed by subsequent inhibition. This inhibition of I (GIRK) by ATP was attenuated by co-expression of regulator of G-protein signaling 2, or phosphatidylinositol-4-phosphate-5-kinase, or intracellular phosphatidylinositol 4,5-bisphosphate loading, but not by the exposure to protein kinase C inhibitors. P2Y(4) stimulation also persistently suppressed the ACh-activated I (GIRK). In addition, I (GIRK) evoked by the stimulation of the P2Y(4) receptor exhibited a transient activation, but that evoked by the stimulation of P2Y(2) or P2Y(12) receptor showed a rather persistent activation. These results reveal (1) that P2Y(1) and P2Y(4) are primarily coupled to the G(q)-phospholipase C-pathway, while being weakly linked to G(i/o), and (2) that P2Y(2) and P2Y(12) involve G(i/o) activation.

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Mechanism of PLC-Mediated Kir3 Current Inhibition

Cited by 49 publications

References 51 publications

Stoichiometry of Kir channels with phosphatidylinositol bisphosphate

Stoichiometry of Kir channels with phosphatidylinositol bisphosphate

A Critical Gating Switch at a Modulatory Site in Neuronal Kir3 Channels

Regulatory mechanisms underlying the modulation of GIRK1/GIRK4 heteromeric channels by P2Y receptors

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