Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the guinea pig.

Fox, Alyson; Barnes, Peter J.; Venkatesan, Priya; Belvisi, Maria G.

doi:10.1172/jci119187

Cited by 101 publications

(51 citation statements)

References 44 publications

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“…The measurement of cough in conscious guinea pigs has been described previously [14][15][16][17]. Terbutaline (0.05-3.0 mg?kg body weight -1 and 1 mL?kg body weight -1 intraperitoneally) or vehicle (0.5% methylcellulose/0.2% Tween 80 in saline) was administered 30 min prior to exposure to capsaicin (1610 -4 M; 5 min) or citric acid (0.3M; 10 min), and the number of coughs over a 10-min period was recorded.…”

Section: Measurement Of Cough In Vivo In the Conscious Guinea Pigmentioning

confidence: 99%

2-Agonists block tussive responses in guinea pigs via an atypical cAMP-dependent pathway

Freund-Michel

Birrell²,

Giembycz³

et al. 2009

European Respiratory Journal

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b 2 -Adrenoceptor agonists are the most effective bronchodilators currently available, and are used for symptom management in asthmatics. However, whether b 2 -agonists are also antitussive is controversial. Identifying an antitussive role for b 2 -agonists and dissecting the possible mechanism of action may help to explain the inconsistencies in the clinical literature and lead to the development of novel therapeutic agents. The aim of the present study was to determine whether or not b 2 -agonists attenuate the tussive response in guinea pig and human models, and, if so, to identify the mechanism(s) involved.Depolarisation of vagal sensory nerves (human and guinea pig) was assessed as an indicator of sensory nerve activity. Cough was measured in a conscious guinea pig model.A b 2 -agonist, terbutaline, dose-dependently inhibited the cough response to tussive agents in conscious guinea pigs. Terbutaline and another b 2 -agonist, fenoterol, blocked sensory nerve activation in vitro. Using these mechanistic models, it was established that b 2 -agonists suppress the tussive response via a nonclassical cyclic adenosine monosphosphate-dependent pathway that involves the activation of protein kinase G and, subsequently, the opening of largeconductance calcium-activated potassium channels.In conclusion, b 2 -adrenoceptor agonists are antitussive, and this property occurs due to a direct inhibition of sensory nerve activation. These findings may help to explain the confusion that exists in the clinical literature, and could be exploited to identify novel therapies for the treatment of cough, which is a significant unmet medical need.

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Section: Measurement Of Cough In Vivo In the Conscious Guinea Pigmentioning

confidence: 99%

2-Agonists block tussive responses in guinea pigs via an atypical cAMP-dependent pathway

Freund-Michel

Birrell²,

Giembycz³

et al. 2009

European Respiratory Journal

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“…They play a key role in the control of neuronal excitability, hormone secretion, and smooth muscle tone (Robitaille et al, 1993;Nelson et al, 1995;Lingle et al, 1996;Fox et al, 1997). Thus, BK Ca channels are considered to be molecular integrators of biochemical and electrical signals.…”

Section: Introductionmentioning

confidence: 99%

Identification and Functional Characterization of Ankyrin-Repeat Family Protein ANKRA as a Protein Interacting with BK_CaChannel

Lim

Park

2005

MBoC

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Ankyrin-repeat family A protein (ANKRA) was originally cloned in mouse as an interacting protein to megalin, a member of low-density lipoprotein receptor superfamily. Here, we report that the isolation of rat ANKRA as a new binding partner for the ␣-subunit of rat large-conductance Ca 2؉ -activated K ؉ channel (rSlo). We mapped the binding region of each protein by using yeast two-hybrid and in vitro binding assays. ANKRA expressed together with rSlo channels were colocalized near the plasma membrane and coimmunoprecipitated in transfected cells. We also showed that BK Ca channel in rat cerebral cortex coprecipitated with rANKRA and colocalized in cultured rat hippocampal neuron. Although the coexpression of ANKRA did not affect the surface expression of rSlo, the gating kinetics of rSlo channel was significantly altered and the effects were highly dependent on the intracellular calcium. These results indicate that ANKRA could modulate the excitability of neurons by binding directly to endogenous BK Ca channel and altering its gating kinetics in a calcium-dependent manner.

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“…They play a key role in the control of neuronal firing (3,4), cell secretion (5), and smooth muscle tone (6). Maxi-K channel activity is under a complex metabolic control that may involve G-proteins (7,8), intracellular Ca 2ϩ concentration (6), and a balance between phosphorylation/dephosphorylation mechanisms (9,10).…”

mentioning

confidence: 99%

The Large Conductance, Voltage-dependent, and Calcium-sensitive K+ Channel, Hslo, Is a Target of cGMP-dependent Protein Kinase Phosphorylation in Vivo

Alioua¹,

Tanaka²,

Wallner³

et al. 1998

Journal of Biological Chemistry

164

129

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Native large conductance, voltage-dependent, and Ca 2؉ -sensitive K ؉ channels are activated by cGMP-dependent protein kinase. Two possible mechanisms of kinase action have been proposed: 1) direct phosphorylation of the channel and 2) indirect via PKG-dependent activation of a phosphatase. To scrutinize the first possibility, at the molecular level, we used the human poreforming ␣-subunit of the Ca 2؉ -sensitive K ؉ channel, Hslo, and the ␣-isoform of cGMP-dependent protein kinase I. In cell-attached patches of oocytes co-expressing the Hslo channel and the kinase, 8-Br-cGMP significantly increased the macroscopic currents. This increase in current was due to an increase in the channel voltage sensitivity by ϳ20 mV and was reversed by alkaline phosphatase treatment after patch excision. In inside-out patches, however, the effect of purified kinase was negative in 12 of 13 patches. In contrast, and consistent with the intact cell experiments, purified kinase applied to the cytoplasmic side of reconstituted channels increased their open probability. This stimulatory effect was absent when heat-denatured kinase was used. Biochemical experiments show that the purified kinase incorporates ␥-33 P into the immunopurified Hslo band of ϳ125 kDa. Furthermore, in vivo phosphorylation largely attenuates this labeling in back-phosphorylation experiments. These results demonstrate that the ␣-subunit of large conductance Ca 2؉ -sensitive K ؉ channels is substrate for G-I␣ kinase in vivo and support direct phosphorylation as a mechanism for PKG-I␣-induced activation of maxi-K channels.

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Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the guinea pig.

Cited by 101 publications

References 44 publications

2-Agonists block tussive responses in guinea pigs via an atypical cAMP-dependent pathway

2-Agonists block tussive responses in guinea pigs via an atypical cAMP-dependent pathway

Identification and Functional Characterization of Ankyrin-Repeat Family Protein ANKRA as a Protein Interacting with BK_CaChannel

The Large Conductance, Voltage-dependent, and Calcium-sensitive K+ Channel, Hslo, Is a Target of cGMP-dependent Protein Kinase Phosphorylation in Vivo

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Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the guinea pig.

Cited by 101 publications

References 44 publications

2-Agonists block tussive responses in guinea pigs via an atypical cAMP-dependent pathway

2-Agonists block tussive responses in guinea pigs via an atypical cAMP-dependent pathway

Identification and Functional Characterization of Ankyrin-Repeat Family Protein ANKRA as a Protein Interacting with BKCaChannel

The Large Conductance, Voltage-dependent, and Calcium-sensitive K+ Channel, Hslo, Is a Target of cGMP-dependent Protein Kinase Phosphorylation in Vivo

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Identification and Functional Characterization of Ankyrin-Repeat Family Protein ANKRA as a Protein Interacting with BK_CaChannel