Signal transduction pathway for the substance P‐induced inhibition of rat Kir3 (GIRK) channel

Koike-Tani, Maki; Collins, John M.; Kawano, Takeharu; Zhao, Peng; Zhao, Qi; Kozasa, Tohru; Nakajima, Shigehiro; Nakajima, Yoshiaki

doi:10.1113/jphysiol.2004.079285

Cited by 22 publications

(32 citation statements)

References 52 publications

(84 reference statements)

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“…Yang et al (2003) concluded that the activation of non-selective ion channels by neurokinins in DRG neurons was independent of G-protein coupling to receptors as it was insensitive to GDP-βS, unlike the modulation of GABA evoked responses by neurokinins. Koike-Tani et al (2005) reported that SP-induced inhibition of Kir3 (GIRK) channels was due to direct binding of Gα q to the channels.…”

Section: Discussionmentioning

confidence: 99%

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Sculptoreanu

Groat

2007

Experimental Neurology

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Neurokinins released by capsaicin-responsive (C-R) dorsal root ganglia neurons (DRG) may control firing in these neurons by an autofeedback mechanism. Here we used patch clamp techniques to examine the effects of neurokinins on firing properties of dissociated DRG neurons of male rats. In C-R neurons that generated only a few action potentials (APs, termed phasic) in response to long depolarizing current pulses (600 ms), substance P (SP, 0.5 μM) lowered the AP threshold by 11.0 ±0.3 mV and increased firing from 1.1±0.7 APs to 5.2±0.6 APs. In C-R tonic neurons that fire multiple APs, SP elicited smaller changes in AP threshold (6.0±0.1 mV reduction) and the number of APs (11±1 vs. 9±1 in control). The effects of SP were similar to the effect of heteropodatoxin II (0.05 μM) or low concentrations of 4-aminopyridine (50 μM) that block A-type K + currents. A selective NK 2 agonist, [βAla 8 ]-neurokinin A (4-10) (0.5 μM), mimicked the effects of SP. The effects of SP in C-R phasic neurons were fully reversed by an NK 2 receptor antagonist (MEN10376, 0.5 μM) but only partially by a protein kinase C (PKC) inhibitor (bisindolylmaleimide, 0.5 μM). An NK 3 selective agonist ([MePhe 7 ]-neurokinin B, 0.5 μM), an NK 1 selective agonist ([Sar 9 , Met 11 ]-substance P, 0.5 μM) or activation of PKC with phorbol 12, 13-dibutyrate (0.5 μM) did not change firing. Our data suggest that the excitability of C-R phasic afferent neurons is increased by activation of NK 2 receptors and intracellular signaling mediated only in part by PKC.

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Section: Discussionmentioning

confidence: 99%

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Sculptoreanu

Groat

2007

Experimental Neurology

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“…A prevailing theory attributes the Kir3 inactivation to lowering of the PIP 2 level in the membrane (Kobrinsky et al, 2000;Cho et al, 2001;Lei et al, 2001) or to the PKC-induced phosphorylation (Sharon et al, 1997;Mao et al, 2004). However, in a previous article (Koike-Tani et al, 2005), we presented evidence that the SP-induced inactivation of Kir3 channels cannot be explained by decline of the PIP 2 level. Increasing the Kir3 affinity to PIP 2 by mutation did not change the SP-induced Kir3 inactivation.…”

mentioning

confidence: 85%

“…It has been shown that G␣ q is involved in the signaling of Kir3 inactivation (Leaney et al, 2001;Lei et al, 2001;Koike-Tani et al, 2005). Beyond this, not much is clarified.…”

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confidence: 99%

Interaction of Gα_qand Kir3, G Protein-Coupled Inwardly Rectifying Potassium Channels

Kawano

Zhao²,

Floreani³

et al. 2007

Mol Pharmacol

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Activation of substance P receptors, which are coupled to G␣ q , inhibits the Kir3.1/3.2 channels, resulting in neuronal excitation. We have shown previously that this channel inactivation is not caused by reduction of the phosphatidylinositol 4,5-bisphosphate level in membrane. Moreover, G␣ q immunoprecipitates with Kir3.2 (J Physiol 564: 489 -500, 2005), suggesting that G␣ q interacts with Kir3.2. Positive immunoprecipitation, however, does not necessarily indicate direct interaction between the two proteins. Here, the glutathione transferase pull-down assay was used to investigate interaction between G␣ q and the K ϩ channels. We found that G␣ q interacted with N termini of Kir3.1, Kir3.2, and Kir3.4. However, G␣ q did not interact with the C terminus of any Kir3 or with the C or N terminus of Kir2.1. TRPC6 is regulated by the signal initiated by G␣ q . Immunoprecipitation, however, showed that G␣ q did not interact with TRPC6. Thus, the interaction between G␣ q and the Kir3 N terminus is quite specific. This interaction occurred in the presence of GDP or GDP-AlF 4 Ϫ . The G␣ q binding could take place somewhere between residues 51 to 90 of Kir3.2; perhaps the segment between 81 to 90 residues is crucial. G␤␥, which is known to bind to N terminus of Kir3, did not compete with G␣ q for the binding, suggesting that these two binding regions are different. These findings agree with the hypothesis (J Physiol 564: 489 -500, 2005) that the signal to inactivate the Kir3 channel could be mainly transmitted directly from G␣ q to Kir3.

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“…In parallel, accumulation of diacylglycerol promotes activation of PKC. The G q -mediated inhibition of GIRK channels arises essentially from the PIP 2 depletion (16 -20, 24, 25) and PKC activation (4,(21)(22)(23), although G␣ q subunits might also contribute directly to this phenomenon (16,33,34). Furthermore, Keselman et al (36) have recently shown that PIP 2 depletion and PKC activation positively reinforced one another in their inhibition of GIRK channels.…”

Section: Discussionmentioning

confidence: 99%

“…Because direct interactions between G␣ q and the neuronal GIRK channels, as well as between G␣ q and the heterologously expressed GIRK1 and GIRK4 subunits, have been recently shown (33,34), we investigated whether G␣ q associates with the GIRK1-G␤ complex following ␣-AR stimulation. G␣ q was detected as a single band of 42 kDa in the atrial membranes.…”

Section: Effects Of ␣-Ar Stimulation On Girk1/4 Channel Function-mentioning

confidence: 99%

Dynamic Integration of α-Adrenergic and Cholinergic Signals in the Atria

Nikolov

Ivanova-Nikolova

2007

Journal of Biological Chemistry

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Numerous heptahelical receptors use activation of heterotrimeric G proteins to convey a multitude of extracellular signals to appropriate effector molecules in the cell. Both high specificity and correct integration of these signals are required for reliable cell function. Yet the molecular machineries that allow each cell to merge information flowing across different receptors are not well understood. Here we demonstrate that G protein-regulated inwardly rectifying K ؉ (GIRK) channels can operate as dynamic integrators of ␣-adrenergic and cholinergic signals in atrial myocytes. Acting at the last step of the cholinergic signaling cascade, these channels are activated by direct interactions with ␤␥ subunits of the inhibitory G proteins (G␤␥), and efficiently translate M 2 muscarinic acetylcholine receptor (M2R) activation into membrane hyperpolarization. The parallel activation of ␣-adrenergic receptors imposed a distinctive "signature" on the function of M2R-activated GIRK1/4 channels, affecting both the probability of G␤␥ binding to the channel and its desensitization. This modulation of channel function was correlated with a parallel depletion of G␤ and protein phosphatase 1 from the oligomeric GIRK1 complexes. Such plasticity of the immediate GIRK signaling environment suggests that multireceptor integration involves large protein networks undergoing dynamic changes upon receptor activation.The heart functions in a continuously changing environment responding to excitatory and inhibitory signals from the sympathetic and parasympathetic branches of autonomic nervous system. Both branches use members of the large family of seven transmembrane G protein-coupled receptors (GPCRs) 2 as membrane gateways for their opposing signals. At rest, parasympathetic signals reduce the heart rate through activation of G i/o -coupled M2Rs. During exercise and stress, sympathetically derived catecholamines target coexisting ARs and increase the cardiac output by accelerating the heart rate and enhancing contractility. The ␤ 1 -, ␤ 2 -, and ␣ 1 -ARs are the most predominant AR subtypes in cardiac myocytes (1). These receptors activate different signaling cascades with ␣ 1 -ARs coupling to G q , ␤ 1 -ARs coupling to G s , and ␤ 2 -ARs coupling to both G s and G i pathways. Although the cellular processes triggered upon activation of individual adrenergic and M 2 receptors have been well delineated (1), how cardiac myocytes integrate the inhibitory and excitatory signals transmitted by these receptors remains less well understood. Signal integration might arise from heterodimerization of members of distinct subfamilies of GPCRs. Such receptor heterodimerization expands the operational features of the receptors involved, modulating either receptor trafficking or function (2). Importantly, heterodimerization of ␤ 1 -and ␤ 2 -ARs in intact cardiac myocytes was recently reported to give rise to a new population of ␤-ARs with enhanced signaling properties (3).Assembly of receptor heterodimers, however, is perhaps only one of the diver...

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Signal transduction pathway for the substance P‐induced inhibition of rat Kir3 (GIRK) channel

Cited by 22 publications

References 52 publications

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Interaction of Gα_qand Kir3, G Protein-Coupled Inwardly Rectifying Potassium Channels

Dynamic Integration of α-Adrenergic and Cholinergic Signals in the Atria

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Signal transduction pathway for the substance P‐induced inhibition of rat Kir3 (GIRK) channel

Cited by 22 publications

References 52 publications

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Interaction of Gαqand Kir3, G Protein-Coupled Inwardly Rectifying Potassium Channels

Dynamic Integration of α-Adrenergic and Cholinergic Signals in the Atria

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Product

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Interaction of Gα_qand Kir3, G Protein-Coupled Inwardly Rectifying Potassium Channels