scholarly journals Calcium Handling in Airway Smooth Muscle: Mechanisms and Therapeutic Implications

1998 ◽  
Vol 5 (6) ◽  
pp. 491-498 ◽  
Author(s):  
Luke J Janssen
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Calcium Handling ◽  
Muscle Physiology ◽  
Therapeutic Implications ◽  
Cellular Processes ◽  
Voltage Dependent ◽  
Complicated Model ◽  
Voltage Dependent Calcium Channels ◽  
Internal Calcium

Calcium plays a central role in the activation of many cellular processes, including the most relevant end-point in airway smooth muscle physiology: contraction. For this reason, the cytosolic concentration of calcium is tightly controlled by an elaborate array of mechanisms. The latter include multiple entry pathways from the extracellular space, a pump on the membrane that extrudes calcium out of the cell, an internal pump that sequesters calcium into an intracellular pool and at least two types of release sites from which sequestered calcium can be released back into the cytosol; all of these mechanisms are tightly regulated by second messenger-signalling pathways. Understanding of the relationship between calcium handling and contraction ("excitation-contraction coupling") has progressed from a mechanism in which activation of voltage-dependent calcium channels plays a central role (as in skeletal muscle) to a mechanism in which a small localized signalling event triggers a massive release of internal calcium (as in cardiac muscle) to a more complicated model in which the internal calcium pool divides the cytosol into two physiologically distinct spaces where the cytosolic concentration of calcium is regulated independently (as in vascular smooth muscle). The changes that may occur in calcium-handling pathways in asthma and the opportunities for novel approaches to the treatment of asthma are also discussed.

BK channel β1-subunit regulation of calcium handling and constriction in tracheal smooth muscle

2006 ◽  
Vol 291 (4) ◽  
pp. L802-L810 ◽  
Author(s):  
Iurii Semenov ◽  
Bin Wang ◽  
Jeremiah T. Herlihy ◽  
Robert Brenner
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Cell Types ◽  
Bk Channels ◽  
Bk Channel ◽  
Tracheal Smooth Muscle ◽  
Calcium Handling ◽  
Cholinergic Signaling ◽  
Smooth Muscle Function ◽  
Voltage Dependent

The large-conductance, Ca2+-activated K+ (BK) channels are regulators of voltage-dependent Ca2+ entry in many cell types. The BK channel accessory β1-subunit promotes channel activation in smooth muscle and is required for proper tone in the vasculature and bladder. However, although BK channels have also been implicated in airway smooth muscle function, their regulation by the β1-subunit has not been investigated. Utilizing the gene-targeted mice for the β1-subunit gene, we have investigated the role of the β1-subunit in tracheal smooth muscle. In mice with the β1-subunit-knockout allele, BK channel activity was significantly reduced in excised tracheal smooth muscle patches and spontaneous BK currents were reduced in whole tracheal smooth muscle cells. Knockout of the β1-subunit resulted in an increase in resting Ca2+ levels and an increase in the sustained component of Ca2+ influx after cholinergic signaling. Tracheal constriction studies demonstrate that the level of constriction is the same with knockout of the β1-subunit and BK channel block with paxillin, indicating that BK channels contribute little to airway relaxation in the absence of the β1-subunit. Utilizing nifedipine, we found that the increased constriction caused by knockout of the β1-subunit could be accounted for by an increased recruitment of L-type voltage-dependent Ca2+ channels. These results indicate that the β1-subunit is required in airway smooth muscle for control of voltage-dependent Ca2+ influx during rest and after cholinergic signaling in BK channels.

Dihydropyridine-sensitive single calcium channels in airway smooth muscle cells

1990 ◽  
Vol 259 (6) ◽  
pp. L468-L480 ◽  
Author(s):  
J. F. Worley ◽  
M. I. Kotlikoff
Keyword(s):  
Smooth Muscle ◽  
Calcium Channels ◽  
Smooth Muscle Cells ◽  
Calcium Channel ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Membrane Depolarization ◽  
Airway Smooth Muscle Cells ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

We have identified and characterized single voltage-dependent calcium channels in both acutely dissociated rat bronchial and cultured human tracheobronchial smooth muscle cells using the patch-clamp technique. In both cell types, on-cell membrane patches displayed unitary currents selective for barium ions and exhibited one conductance level (21–26 pS), and the open state probability was increased by membrane depolarization. Unitary barium currents were enhanced by the calcium channel selective agonist, BAY R 5417, and inhibited by the dihydropyridine calcium channel antagonist, nisoldipine (apparent inhibition constant less than 100 nM). Moreover, the degree of nisoldipine inhibition of the rat bronchial smooth muscle channels was increased with membrane depolarization in a manner consistent with the drug interacting with highest affinity to the inactivated channel state. In addition, the sensitivity to BAY R 5417 augmentation and nisoldipine inhibition of depolarization-induced tonic force of intact rat bronchial ring segments was in close agreement to the single channel results. Thus these data suggest that activation of voltage-dependent calcium channels can influence airway contraction and that dihydropyridines may be effective modulators of depolarization-induced increases in bronchial tone. We conclude that both rat and human airway smooth muscle cells have high-conductance voltage-dependent calcium channels that interact in a predictable manner with dihydropyridines and are similar to voltage-dependent calcium channels observed in other smooth muscle cells.

scholarly journals Chloride in airway smooth muscle: the ignored anion no longer?

2012 ◽  
Vol 302 (8) ◽  
pp. L733-L735 ◽  
Author(s):  
George Gallos ◽  
Peter Yim ◽  
Charles W. Emala
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Calcium Handling ◽  
Muscle Physiology ◽  
Smooth Muscle Contractility ◽  
Chloride Currents ◽  
New Developments ◽  
Mediated Effects

This Perspectives accompanies an Editorial Focus that summarizes new developments concerning the role of chloride in airway smooth muscle physiology. We provide several observations and mechanistic insights to reconcile recent experimental evidence with existing paradigms concerning chloride channel-mediated effects on airway smooth muscle tone. In addition, we highlight the potentially complex and dynamic nature that chloride currents and membrane potential have on calcium handling and airway smooth muscle contractility.

MgSO4 relaxes porcine airway smooth muscle by reducing Ca2+ entry

1996 ◽  
Vol 270 (3) ◽  
pp. L469-L474 ◽  
Author(s):  
D. Kumasaka ◽  
K. S. Lindeman ◽  
J. Clancy ◽  
B. Lande ◽  
T. L. Croxton ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Mechanism Of Action ◽  
Muscle Tension ◽  
Isometric Tension ◽  
Free Calcium ◽  
Response Curves ◽  
Rightward Shift ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

Magnesium sulfate (MgSO4) is used clinically, but its mechanism of action is unknown. To determine whether MgSO4 relaxes airway smooth muscle and to investigate the pathways involved, we compared effects of MgSO4 in porcine tracheal and bronchial muscles contracted with either carbachol or KCl and measured the effects of MgSO4 on the concentration of intracellular free calcium ([Ca2+]i). Lungs were dissected after anesthesia and exsanguination. Tracheal strips and bronchial rings were suspended in tissue baths for measurement of isometric tension in the presence of different concentrations of MgSO4. In separate experiments, tracheal smooth muscle tension and [Ca2+]i were measured simultaneously, using the fluorescent dye fura 2. MgSO4 (1.2, 2.2, 9.2 mM) produced a concentration dependent rightward shift of contraction dose-response curves to KCl but not to carbachol. MgSO4 relaxed trachealis muscles precontracted with KCl or carbachol and simultaneously decreased [Ca2+]i. These findings indicate that MgSO4 directly relaxes airway smooth muscle and that the mechanism involves a decrease in [Ca2+]i. Because initiation and maintenance of contraction during KCl stimulation and maintenance of contraction during carbachol stimulation require Ca2+ entry through voltage-dependent calcium channels, MgSO4-induced relaxation may involve a decrease in Ca2+ entry via these channels.

Inhibition of dihydropyridine-sensitive calcium entry in hypoxic relaxation of airway smooth muscle

1995 ◽  
Vol 268 (2) ◽  
pp. L201-L206 ◽  
Author(s):  
C. Vannier ◽  
T. L. Croxton ◽  
L. S. Farley ◽  
C. A. Hirshman
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Bay K 8644 ◽  
O2 Concentration ◽  
Voltage Dependent ◽  
Progressive Hypoxia ◽  
Carbamyl Choline

Hypoxia dilates airways in vivo and reduces active tension of airway smooth muscle in vitro. To determine whether hypoxia impairs Ca2+ entry through voltage-dependent channels (VDC), we tested the ability of dihydropyridines to modulate hypoxia-induced relaxation of KCl- and carbamyl choline (carbachol)-contracted porcine bronchi. Carbachol- or KCl-contracted bronchial rings were exposed to progressive hypoxia in the presence or absence of 1 microM BAY K 8644 (an L-type-channel agonist). In separate experiments, rings were contracted with carbachol or KCl, treated with nifedipine (a VDC antagonist), and finally exposed to hypoxia. BAY K 8644 prevented hypoxia-induced relaxation in KCl-contracted bronchi. Nifedipine (10(-5) M) totally relaxed KCl- contracted bronchi. Carbachol-contracted bronchi were only partially relaxed by nifedipine but were completely relaxed when the O2 concentration of the gas was reduced from 95 to 0%. These data indicate that hypoxia can reduce airway smooth muscle tone by limiting entry of Ca2+ through a dihydropyridine-sensitive pathway, but that other mechanisms also contribute to hypoxia-induced relaxation of carbachol-contracted bronchi.

scholarly journals Membrane Currents in Airway Smooth Muscle: Mechanisms and Therapeutic Implications

1997 ◽  
Vol 4 (1) ◽  
pp. 13-20
Author(s):  
Luke J Janssen
Keyword(s):  
Smooth Muscle ◽  
Ion Channels ◽  
Calcium Channels ◽  
Airway Smooth Muscle ◽  
Calcium Ion ◽  
Membrane Conductance ◽  
Chloride Ion ◽  
Potassium Ion Channels ◽  
Therapeutic Implications ◽  
Transient Activation

Electrophysiological and pharmacological techniques were used to characterize the membrane conductance changes underlying spasmogen-evoked depolarization in airway smooth muscle (ASM). Changes included a transient activation of chloride ion channels and prolonged suppression of potassium ion channels; both changes are triggered by release of internally sequestered calcium ion and in turn cause opening of voltage-dependent calcium channels. The resultant influx of calcium ions contributes to contraction as well as to refilling of the internal calcium ion pool. Bronchodilators, on the other hand, act in part through activation of potassium channels, with consequent closure of calcium channels. The tools used to study ion channels in ASM are described, and the investigations of the roles of ion channels in ASM physiology (autacoid-evoked depolarization and hyperpolarization) and pathophysiology (airway hyperresponsiveness) are summarized. Finally, how the relationship between ion channels and ASM function/dysfunction may relate to the treatment of asthma and related breathing disorders is discussed.

Expression of dihydropyridine resistance differs in porcine bronchial and tracheal smooth muscle

1994 ◽  
Vol 267 (2) ◽  
pp. L106-L112 ◽  
Author(s):  
T. L. Croxton ◽  
C. Fleming ◽  
C. A. Hirshman
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Isometric Tension ◽  
Tracheal Smooth Muscle ◽  
Airway Smooth Muscle Cells ◽  
Channel Blockers ◽  
Response Curves ◽  
Voltage Dependent ◽  
Relaxation Responses ◽  
Ca2 Channels

Voltage-dependent and receptor-operated Ca2+ entry mechanisms have been demonstrated in airway smooth muscle, but their relative importance for maintenance of contraction is unknown. Blockade of voltage-dependent Ca2+ channels (VDC) has produced inconsistent relaxation. We postulated regional variations in Ca2+ handling by airway smooth muscle cells and compared the efficacy of dihydropyridine VDC blockers in tracheas and bronchi. Porcine tracheal smooth muscle strips and bronchial rings were mounted in tissue baths filled with physiological solutions and isometric tension was measured. Tissues were precontracted with carbachol or KCl, and relaxation dose-response curves to nifedipine, Mn2+, or Cd2+ were obtained. Relaxation responses to nifedipine were significantly different in carbachol-contracted tracheas and bronchi. Whereas carbachol-contracted tracheal muscle completely relaxed with 10(-6) M nifedipine, bronchial smooth muscle relaxed < 50%. In contrast, KCl-contracted bronchial muscle was completely relaxed by nifedipine. The nonspecific Ca2+ channel blockers Mn2+ and Cd2+ produced similar relaxation responses in each tissue. Thus VDC are the predominant mechanism for Ca2+ entry in porcine tracheal smooth muscle, but a dihydropyridine-insensitive pathway is functionally important in carbachol-contracted porcine bronchi. Regional variation may account for apparent inconsistencies between previous studies.

Endothelium modulates anion channel-dependent aortic contractions to iodide

2000 ◽  
Vol 278 (5) ◽  
pp. H1527-H1536 ◽  
Author(s):  
Fred S. Lamb ◽  
Thomas J. Barna
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Membrane Potential ◽  
Anion Channel ◽  
Anion Channels ◽  
Anion Substitution ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Channel Dependent ◽  
Cytochrome P 450

Anion currents contribute to vascular smooth muscle (VSM) membrane potential. The substitution of extracellular chloride (Cl) with iodide (I) or bromide (Br) initially inhibited and then potentiated isometric contractile responses of rat aortic rings to norepinephrine. Anion substitution alone produced a small relaxation, which occurred despite a lack of active tone and minimal subsequent contraction of endothelium-intact rings (4.2 ± 1.2% of the response to 90 mM KCl). Endothelium-denuded rings underwent a similar initial relaxation but then contracted vigorously (I > Br). Responses to 130 mM I (93.7 ± 1.9% of 90 mM KCl) were inhibited by nifedipine (10− 6 M), niflumic acid (10− 5 M), tamoxifen (10− 5 M), DIDS (10− 4 M), and[Formula: see text]-free buffer (HEPES 10 mM) but not by bumetanide (10− 5 M). Intact rings treated with N ω-nitro-l-arginine (10− 4 M) responded weakly to I (15.5 ± 2.1% of 90 mM KCl), whereas hemoglobin (10− 5 M), indomethacin (10− 6 M), 17-octadecynoic acid (10− 5 M), and 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10− 6 M) all failed to augment the response of intact rings to I. We hypothesize that VSM takes up I primarily via an anion exchanger. Subsequent I efflux through anion channels having a selectivity of I > Br > Cl produces depolarization. In endothelium-denuded or agonist-stimulated vessels, this current is sufficient to activate voltage-dependent calcium channels and cause contraction. Neither nitric oxide nor prostaglandins are the primary endothelial modulator of these anion channels. If they are regulated by an endothelium-dependent hyperpolarizing factor it is not a cytochrome P-450 metabolite.

scholarly journals Estrogen receptors differentially regulate intracellular calcium handling in human nonasthmatic and asthmatic airway smooth muscle cells

2020 ◽  
Vol 318 (1) ◽  
pp. L112-L124 ◽  
Author(s):  
Sangeeta Bhallamudi ◽  
Jennifer Connell ◽  
Christina M Pabelick ◽  
Y. S. Prakash ◽  
Venkatachalem Sathish
Keyword(s):  
Smooth Muscle ◽  
Estrogen Receptors ◽  
Intracellular Calcium ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Clinical Findings ◽  
Calcium Handling ◽  
Airway Smooth Muscle Cells ◽  
Adult Women ◽  
Channel Inhibition

Asthma is defined as chronic inflammation of the airways and is characterized by airway remodeling, hyperresponsiveness, and acute bronchoconstriction of airway smooth muscle (ASM) cells. Clinical findings suggest a higher incidence and severity of asthma in adult women, indicating a concrete role of sex steroids in modulating the airway tone. Estrogen, a major female sex steroid mediates its role through estrogen receptors (ER) ERα and ERβ, which are shown to be expressed in human ASM, and their expression is upregulated in lung inflammation and asthma. Previous studies suggested rapid, nongenomic signaling of estrogen via ERs reduces intracellular calcium ([Ca2+]i), thereby promoting relaxation of ASM. However, long-term ER activation on [Ca2+]i regulation in human ASM during inflammation or in asthma is still not known. In Fura-2-loaded nonasthmatic and asthmatic human ASM cells, we found that prolonged (24 h) exposure to ERα agonist (PPT) increased [Ca2+]i response to histamine, whereas ERβ activation (WAY) led to decreased [Ca2+] compared with vehicle. This was further confirmed by ER overexpression and knockdown studies using various bronchoconstrictor agents. Interestingly, ERβ activation was more effective than 17β-estradiol in reducing [Ca2+]i responses in the presence of TNF-α or IL-13, while no observable changes were noticed with PPT in the presence of either cytokine. The [Ca2+]i-reducing effects of ERβ were mediated partially via L-type calcium channel inhibition and increased Ca2+ sequestration by sarcoplasmic reticulum. Overall, these data highlight the differential signaling of ERα and ERβ in ASM during inflammation. Specific ERβ activation reduces [Ca2+]i in the inflamed ASM cells and is likely to play a crucial role in regulating ASM contractility, thereby relaxing airways.

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