Ionic mechanisms and Ca2+ handling in airway smooth muscle

Hirota, Simon A.; Helli, Peter B.; Janssen, Luke J.

doi:10.1183/09031936.00147706

Cited by 76 publications

(75 citation statements)

References 187 publications

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“…Apparently, the inhibited activity of NSCCs can be explained by a reduction in the functional TRPC3-encoded channels. The resting Vm normally is between -40 and -50 mV in ASMCs, which is to a great extent less negative than the K 1 equilibrium potential of approximately 285 mV (11,12). It has been shown that native NSCCs are associated with the less negative resting Vm in rabbit pulmonary and coronary artery SMCs (9,10).…”

Section: Discussionmentioning

confidence: 99%

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Functional Role of Canonical Transient Receptor Potential 1 and Canonical Transient Receptor Potential 3 in Normal and Asthmatic Airway Smooth Muscle Cells

Xiao

Zheng

Liao

et al. 2010

Am J Respir Cell Mol Biol

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Canonical transient receptor potential (TRPC)-encoded nonselective cation channels (NSCCs) are crucial for many cellular responses in a variety of cells; however, their molecular expression and functional roles in airway smooth muscle cells (ASMCs) remain obscure. The objective of this study was to determine whether TRPC1 and TRPC3 molecules could be important molecular constituents of native NSCCs controlling the resting membrane potential (Vm) and [Ca 21 ] i in freshly isolated normal and ovalbumin (OVA)-sensitized/-challenged mouse ASMCs. Western blotting, RT-PCR, single-channel recording, whole-cell current-clamp recording, and a fluorescence imaging system were used to determine TRPC expression, NSCC activity, resting Vm, and resting [Ca 21 ] i . Specific individual TRPC antibodies and siRNAs were applied to test their functional roles. TRPC1 and TRPC3 proteins and mRNAs were expressed in freshly isolated ASM tissues. TRPC3 antibodies blocked the activity of NSCCs and hyperpolarized the resting Vm in ASMCs, whereas TRPC1 antibodies had no effect. TRPC3, but not TRPC1 gene silencing, largely diminished NSCC activity, hyperpolarized the resting Vm, lowered the resting [Ca 21 ] i , and inhibited methacholine-induced increase in [Ca 21 ] i . In OVA-sensitized/-challenged ASMCs, NSCC activity was greatly augmented, resting Vm was depolarized, and TRPC3 protein expression was increased. TRPC1 and TRPC3 antibodies blocked the increased activity of NSCCs and membrane depolarization in OVA-sensitized/-challenged cells. TRPC3 is an important molecular component of native NSCCs contributing to the resting Vm and [Ca 21 ] i in normal ASMCs, as well as membrane depolarization and hyperresponsiveness in OVA-sensitized/ -challenged cells, whereas TRPC1-encoded NSCCs are only activated in OVA-sensitized/-challenged airway myocytes.

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Section: Discussionmentioning

confidence: 99%

“…Although the underlying mechanisms are being investigated, membrane depolarization has been found in ovalbumin-sensitized/challenged ASMCs (11,12). Presumably, membrane depolarization may increase the cell excitability and sensitivity to contractile agonists or can cause extracellular Ca 21 influx, contributing to airway muscle hyperresponsiveness.…”

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confidence: 99%

Functional Role of Canonical Transient Receptor Potential 1 and Canonical Transient Receptor Potential 3 in Normal and Asthmatic Airway Smooth Muscle Cells

Xiao

Zheng

Liao

et al. 2010

Am J Respir Cell Mol Biol

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“…There is evidence that plasma membrane Ca 2ϩ dependent Cl Ϫ channels are activated in ASM after procontractile stimuli and can allow for the egress of chloride out of the cell (12,40), which not only promotes plasma membrane depolarization, but may also provide a favorable gradient for subsequent sarcolemmal Ca 2ϩ handling during procontractile stimuli (9). Recent evidence Fig.…”

Section: Discussionmentioning

confidence: 99%

Activation of endogenous GABA_A channels on airway smooth muscle potentiates isoproterenol-mediated relaxation

Gallos¹,

Gleason²,

Zhang³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Emala CW. Activation of endogenous GABAA channels on airway smooth muscle potentiates isoproterenol-mediated relaxation. Am J Physiol Lung Cell Mol Physiol 295: L1040 -L1047, 2008. First published September 12, 2008 doi:10.1152/ajplung.90330.2008.-Reactive airway disease predisposes patients to episodes of acute smooth muscle mediated bronchoconstriction. We have for the first time recently demonstrated the expression and function of endogenous ionotropic GABAA channels on airway smooth muscle cells. We questioned whether endogenous GABAA channels on airway smooth muscle could augment ␤-agonist-mediated relaxation. Guinea pig tracheal rings or human bronchial airway smooth muscles were equilibrated in organ baths with continuous digital tension recordings. After pretreatment with or without the selective GABAA antagonist gabazine (100 M), airway muscle was contracted with acetylcholine or ␤-ala neurokinin A, followed by relaxation induced by cumulatively increasing concentrations of isoproterenol (1 nM to 1 M) in the absence or presence of the selective GABAA agonist muscimol (10 -100 M). In separate experiments, guinea pig tracheal rings were pretreated with the large conductance KCa channel blocker iberiotoxin (100 nM) after an EC50 contraction with acetylcholine but before cumulatively increasing concentrations of isoproterenol (1 nM to 1 uM) in the absence or presence of muscimol (100 uM). GABAA activation potentiated the relaxant effects of isoproterenol after an acetylcholine or tachykinin-induced contraction in guinea pig tracheal rings or an acetylcholine-induced contraction in human endobronchial smooth muscle. This muscimol-induced potentiation of relaxation was abolished by gabazine pretreatment but persisted after blockade of the maxi KCa channel. Selective activation of endogenous GABAA receptors significantly augments ␤-agonist-mediated relaxation of guinea pig and human airway smooth muscle, which may have important therapeutic implications for patients in severe bronchospasm. guinea pig; organ bath; gabazine; muscimol ASTHMA IS A CHRONIC inflammatory disease of the airways the prevalence of which both in the United States and throughout much of the world has taken on pandemic proportions (4). Standard treatment for asthma centers on pharmacological attenuation of hyperresponsiveness either by modulation of inflammatory mediators or by promoting airway smooth muscle (ASM) relaxation (e.g., ␤ 2 -adrenoceptor agonists). Although research over the past three decades has made great strides in elucidating many of the underlying mechanisms involved in this disease, few novel additions to the pharmacological armamentarium have occurred in the treatment of reactive airway disease.␤ 2 -Adrenoceptor agonists retain a prominent role in the clinical treatment of airway hyperresponsiveness, and the mechanisms by which ␤ 2 -adrenoceptor agonists relax ASM include both cAMP-dependent and cAMP-independent pathways. Additionally, regulation of ␤ 2 -adrenoceptor activity either through desensitization or downregu...

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“…Important advances have been made in the current understanding of the mechanisms underlying these Ca 2+ oscillations. These have been described in far greater detail than is possible here [36,37,40,41], and the biophysical and pharmacological properties of the cellular machines (pumps and channels) involved in triggering and propagating these Ca 2+ waves have been reviewed elsewhere [42,43]. The present study simply introduces the various cellular entities which are involved.…”

Section: Where Do We Go Next?mentioning

confidence: 99%

Asthma therapy: how far have we come, why did we fail and where should we go next?

Janssen¹

2009

European Respiratory Journal

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Reversible airflow obstruction and nonspecific airway hyperresponsiveness are: 1) the two key features of asthma; 2) the primary concern for asthma patients; and 3) both directly caused by the airway smooth muscle (ASM). As such, controlling bronchoconstriction should be of primary importance. Unfortunately, all existing pharmacological asthma therapies that specifically target the ASM are based on decades old strategies.In the present study, the evolution of pharmacological asthma therapy will be briefly discussed, some explanations will be suggested as to why substantial new advances in this area have not occurred in several years and, finally, several new directions for novel asthma therapies will be proposed.

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Ionic mechanisms and Ca2+ handling in airway smooth muscle

Cited by 76 publications

References 187 publications

Functional Role of Canonical Transient Receptor Potential 1 and Canonical Transient Receptor Potential 3 in Normal and Asthmatic Airway Smooth Muscle Cells

Functional Role of Canonical Transient Receptor Potential 1 and Canonical Transient Receptor Potential 3 in Normal and Asthmatic Airway Smooth Muscle Cells

Activation of endogenous GABA_A channels on airway smooth muscle potentiates isoproterenol-mediated relaxation

Asthma therapy: how far have we come, why did we fail and where should we go next?

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