Bombesin Receptors Inhibit G Protein-Coupled Inwardly Rectifying K<sup>+</sup>Channels Expressed in<i>Xenopus</i>Oocytes through a Protein Kinase C-Dependent Pathway

Stevens, Edward B.; Shah, Bhaval S.; Pinnock, R.D.; Lee, Kevin

doi:10.1124/mol.55.6.1020

Cited by 45 publications

(40 citation statements)

References 36 publications

(51 reference statements)

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“…[2][3][4][5][6][7][8] The mechanism by which PLC activation leads to current inhibition has been attributed to either direct PIP 2 depletion from the channel 2,9-11 or PKC-mediated effects. [12][13][14][15][16][17][18] Kir3 channels are G-protein regulated, K + selective, inwardly rectifying channels expressed in cardiac, neuronal and endocrine cells, where they play an important role in regulating membrane excitability. 19,20 These channels are regulated by direct binding of the G-protein-bg subunits 21 and, like all members of the Kir channel family, are dependent on PIP 2 for activity.…”

Section: Introductionmentioning

confidence: 99%

“…As with other PIP 2 -dependent channel families, both depletion of PIP 2 and downstream activation of PKC have been shown to be involved in Kir inhibition but the exact roles of PIP 2 and PKC and the extent to which they contribute to current inhibition remains controversial. 2,5,9,[12][13][14]17,18,[26][27][28][29][30][31][32][33] Moreover, PKC activation independently of PIP 2 hydrolysis has been shown by several laboratories to lead to current inhibition, but the mechanism of PKC-mediated current inhibition remains controversial, despite extensive efforts. 17 In the present work we studied the roles of direct PIP 2 depletion and PKC action and addressed the interdependent contributions of these mechanisms in Kir3 current inhibition.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of PLC-Mediated Kir3 Current Inhibition

Keselman¹,

Fribourg²,

Felsenfeld³

et al. 2007

Channels

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A large number of ion channels maintain their activity through direct interactions with phosphatidylinositol bisphosphate (PIP 2 ). For such channels, hydrolysis of PIP 2 causes current inhibition. It has become controversial whether the inhibitory effects on channel activity represent direct effects of PIP 2 hydrolysis or of downstream PKC action. We studied Phospholipase C (PLC)-dependent inhibition of G protein-activated inwardly rectifying K + (Kir3) channels. By monitoring simultaneously channel activity and PIP 2 hydrolysis, we determined that both direct PIP 2 depletion and PKC actions contribute to Kir3 current inhibition. We show that the PKC-induced effects strongly depend on PIP 2 levels in the membrane. At the same time, we show that PKC destabilizes Kir3/PIP 2 interactions and enhances the effects of PIP 2 depletion on channel activity. These results demonstrate that PIP 2 depletion and PKC-mediated effects reinforce each other and suggest that both of these interdependent mechanisms contribute to Kir3 current inhibition. This mechanistic insight may explain how even minor changes in PIP 2 levels can have profound effects on Kir3 activity. We also show that stabilization of Kir3/PIP 2 interactions by Gbg attenuates both PKC and Gq-mediated current inhibition, suggesting that diverse pathways regulate Kir3 activity through modulation of channel interactions with PIP 2 .

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanism of PLC-Mediated Kir3 Current Inhibition

Keselman¹,

Fribourg²,

Felsenfeld³

et al. 2007

Channels

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“…Second, PIP 2 is hydrolyzed by PLC to form IP 3 and diacylglycerol (DAG). DAG activates protein kinase C (PKC), which can also inhibit K ir channel activity (Mao et al 2004;Stevens et al 1999) that should also decrease the inward rectification. Given the above, we propose that the D 2 Rmediated reduction in the inward rectification (representing decreased I Kir ) should be attributed to activation of PI-PLC and a consequent reduction of intracellular PIP 2 levels.…”

Section: R-mediated Attenuation Of Inward Rectification Is Modulamentioning

confidence: 99%

Dopamine D₂ Receptor Modulation of K⁺ Channel Activity Regulates Excitability of Nucleus Accumbens Neurons at Different Membrane Potentials

Pérez¹,

White²,

Hu³

2006

Journal of Neurophysiology

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receptor modulation of K ϩ channel activity regulates excitability of nucleus accumbens neurons at different membrane potentials. J Neurophysiol 96: 2217-2228, 2006. First published August 2, 2006 doi:10.1152/jn.00254.2006. The nucleus accumbens (NAc) is a forebrain area in the mesocorticolimbic dopamine (DA) system that regulates many aspects of drug addiction. Neuronal activity in the NAc is modulated by different subtypes of DA receptors. Although DA signaling has received considerable attention, the mechanisms underlying D 2 -class receptor (D 2 R) modulation of firing in medium spiny neurons (MSNs) localized within the NAc remain ambiguous. In the present study, we performed whole cell current-clamp recordings in rat brain slices to determine whether and how D 2 R modulation of K ϩ channel activity regulates the intrinsic excitability of NAc neurons in the core region. D 2 R stimulation by quinpirole or DA significantly and dose-dependently decreased evoked Na ϩ spikes. This D 2 R effect on inhibiting evoked firing was abolished by antagonism of D 2 Rs, reversed by blockade of voltage-sensitive, slowly inactivating A-type K ϩ currents (I As ), or eliminated by holding membrane potentials at levels in which I As was inactivated. It was also mimicked by inhibition of cAMP-dependent protein kinase (PKA) activity, but not phosphatidylinositol-specific phospholipase C (PI-PLC) activity. Moreover, D 2 R stimulation also reduced the inward rectification and depolarized the resting membrane potentials (RMPs) by decreasing "leak" K ϩ currents. However, the D 2 R effects on inward rectification and RMP were blocked by inhibition of PI-PLC, but not PKA activity. These findings indicate that, with facilitated intracellular Ca 2ϩ release and activation of the D 2 R/G q /PLC/PIP 2 pathway, the D 2 R-modulated changes in the NAc excitability are dynamically regulated and integrated by multiple K ϩ currents, including but are not limited to I As , inwardly rectifying K ϩ currents (I Kir ), and "leak" currents (I K-2P ).

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“…PIP 2 has been shown to directly interact with the C terminus of the GIRK channels and activate the channels as a membrane-delimited second messenger (5). GIRK channels have also been shown to be modulated by other factors such as mechanical stretch (6) and protein kinase C (PKC) (3,7), although an involvement of PIP 2 is not known.…”

mentioning

confidence: 99%

Mechanosensitivity of GIRK Channels Is Mediated by Protein Kinase C-dependent Channel-Phosphatidylinositol 4,5-Bisphosphate Interaction

Zhang

Lee

John

et al. 2004

Journal of Biological Chemistry

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Gprotein-activated inwardly rectifying K ؉ channel (GIRK or Kir3) currents are inhibited by mechanical stretch of the cell membrane, but the underlying mechanisms are not understood. In Xenopus oocytes heterologously expressing GIRK channels, membrane stretch induced by 50% reduction of osmotic pressure caused a prompt reduction of GIRK1/4, GIRK1, and GIRK4 currents by 16.6 -42.6%. Comparable GIRK current reduction was produced by protein kinase C (PKC) activation (phorbol 12-myristate 13-acetate). The mechanosensitivity of the GIRK4 current was abolished by pretreatment with PKC inhibitors (staurosporine or calphostin C). Neither hypo-osmotic challenge nor PKC activation affected IRK1 currents. GIRK4 chimera (GIRK4-IRK1-(Lys 207 -Leu 245 )) and single point mutant (GIRK4(I229L)), in which the phosphatidylinositol 4,5-bisphosphate (PIP 2 ) binding domain or residue was replaced by the corresponding region of IRK1 to strengthen the channel-PIP 2 interaction, showed no mechanosensitivity and minimal PKC sensitivity. IRK1 gained mechanosensitivity and PKC sensitivity by reverse double point mutation of the PIP 2 binding domain (L222I/R213Q). Overexpression of G␤␥, which is known to strengthen the channel-PIP 2 interaction, attenuated the mechanosensitivity of GIRK4 channels. In oocytes expressing a pleckstrin homology domain of PLC-␦ tagged with green fluorescent protein, hypo-osmotic challenge or PKC activation caused a translocation of the fluorescence signal from the cell membrane to the cytosol, reflecting PIP 2 hydrolysis. The translocation was prevented by pretreatment with PKC inhibitors. Involvement of PKC activation in the mechanosensitivity of muscarinic K ؉ channels was confirmed in native rabbit atrial myocytes. These results suggest that the mechanosensitivity of GIRK channels is mediated primarily by channel-PIP 2 interaction, with PKC playing an important role in modulating the interaction probably through PIP 2 hydrolysis.Muscarinic K ϩ (K ACh ) 1 channels in the heart are heterotetrameric channels composed of two subunits, GIRK1 (Kir3.1) and GIRK4 (Kir3.4) (1). The K ACh channels are stimulated by M 2 receptor activation in response to parasympathetic stimulation, which leads to the hyperpolarization of the membrane potential and results in a decreased heart rate (2, 3). In addition to this canonical activating pathway, molecules such as G␤␥, intracellular Na ϩ , and Mg 2ϩ also activate the GIRK channels by strengthening the phosphatidylinositol 4,5-bisphosphate (PIP 2 ) interaction with the channels (4). PIP 2 has been shown to directly interact with the C terminus of the GIRK channels and activate the channels as a membrane-delimited second messenger (5). GIRK channels have also been shown to be modulated by other factors such as mechanical stretch (6) and protein kinase C (PKC) (3, 7), although an involvement of PIP 2 is not known.Mechanical stimuli alter the electrophysiological properties of the heart. This mechanoelectrical feedback plays important roles in regulating cardiac function (8, 9)....

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Bombesin Receptors Inhibit G Protein-Coupled Inwardly Rectifying K⁺Channels Expressed inXenopusOocytes through a Protein Kinase C-Dependent Pathway

Cited by 45 publications

References 36 publications

Mechanism of PLC-Mediated Kir3 Current Inhibition

Mechanism of PLC-Mediated Kir3 Current Inhibition

Dopamine D₂ Receptor Modulation of K⁺ Channel Activity Regulates Excitability of Nucleus Accumbens Neurons at Different Membrane Potentials

Mechanosensitivity of GIRK Channels Is Mediated by Protein Kinase C-dependent Channel-Phosphatidylinositol 4,5-Bisphosphate Interaction

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Bombesin Receptors Inhibit G Protein-Coupled Inwardly Rectifying K+Channels Expressed inXenopusOocytes through a Protein Kinase C-Dependent Pathway

Cited by 45 publications

References 36 publications

Mechanism of PLC-Mediated Kir3 Current Inhibition

Mechanism of PLC-Mediated Kir3 Current Inhibition

Dopamine D2 Receptor Modulation of K+ Channel Activity Regulates Excitability of Nucleus Accumbens Neurons at Different Membrane Potentials

Mechanosensitivity of GIRK Channels Is Mediated by Protein Kinase C-dependent Channel-Phosphatidylinositol 4,5-Bisphosphate Interaction

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Bombesin Receptors Inhibit G Protein-Coupled Inwardly Rectifying K⁺Channels Expressed inXenopusOocytes through a Protein Kinase C-Dependent Pathway

Dopamine D₂ Receptor Modulation of K⁺ Channel Activity Regulates Excitability of Nucleus Accumbens Neurons at Different Membrane Potentials