Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction.
Yocum GT
,
Gallos G
,
Zhang Y
,
Jahan R
,
Stephen MR
,
Varagic Z
,
Puthenkalam R
,
Ernst M
,
Cook JM
,
Emala CW
.
???displayArticle.abstract???
We previously demonstrated that airway smooth muscle (ASM) cells express γ-aminobutyric acid A receptors (GABA(A)Rs), and that GABA(A)R agonists acutely relax ASM. Among the GABA(A)R α subunits, human ASM cells express only α4 and α5, providing the opportunity for selective pharmacologic targeting. Novel GABA(A)R-positive allosteric modulators designed for enhanced α4/α6 subunit selectivity were synthesized using iterative computational analyses (CMD-45 and XHe-III-74). Studies using oocyte heterologous expression systems confirmed that CMD-45 and XHe-III-74 led to significantly greater augmentation of currents induced by a 3% maximal effective concentration (EC3) of GABA [EC3]-induced currents in oocytes expressing α4 or α6 subunits (along with β3 and γ2) compared with other α subunits. CMD-45 and XHe-III-74 also led to greater ex vivo relaxation of contracted wild-type mouse tracheal rings compared with tracheal rings from GABA(A)R α4 subunit (Gabra4) knockout mice. Furthermore, CMD-45 and XHe-III-74 significantly relaxed precontracted human ASM ex vivo, and, at a low concentration, both ligands led to a significant leftward shift in albuterol-mediated ASM relaxation. In vivo, inhaled XHe-III-74 reduced respiratory system resistance in an asthmatic mouse model. Pretreatment of human ASM cells with CMD-45 and XHe-III-74 inhibited histamine-induced increases in intracellular calcium concentrations in vitro, an effect that was lost when calcium was omitted from the extracellular buffer, suggesting that inhibition of calcium influx due to alterations in plasma membrane potential may play a role in the mechanism of ASM relaxation. Selective targeting of the GABA(A)R α4 subunit with inhaled ligands may be a novel therapeutic pathway to treat bronchoconstriction, while avoiding sedative central nervous system effects, which are largely mediated by α1-3 subunit-containing GABA(A)Rs in the brain.
Bencsits,
A significant part of native gamma-aminobutyric AcidA receptors containing alpha4 subunits do not contain gamma or delta subunits.
1999, Pubmed
Bencsits,
A significant part of native gamma-aminobutyric AcidA receptors containing alpha4 subunits do not contain gamma or delta subunits.
1999,
Pubmed
Bhagat,
Rapid onset of tolerance to the bronchoprotective effect of salmeterol.
1995,
Pubmed
Chandra,
GABAA receptor alpha 4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol.
2006,
Pubmed
Chu,
Asthma: one hundred years of treatment and onward.
2005,
Pubmed
Corburn,
Urban asthma and the neighbourhood environment in New York City.
2006,
Pubmed
Gallos,
Activation of endogenous GABAA channels on airway smooth muscle potentiates isoproterenol-mediated relaxation.
2008,
Pubmed
Gallos,
Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling.
2015,
Pubmed
Gallos,
Targeting the restricted α-subunit repertoire of airway smooth muscle GABAA receptors augments airway smooth muscle relaxation.
2012,
Pubmed
Giannini,
Tolerance to the protective effect of salmeterol on allergen challenge can be partially restored by the withdrawal of salmeterol regular treatment.
2001,
Pubmed
Hirota,
Store-refilling involves both L-type calcium channels and reverse-mode sodium-calcium exchange in airway smooth muscle.
2007,
Pubmed
Hirota,
Ionic mechanisms and Ca2+ handling in airway smooth muscle.
2007,
Pubmed
Hirota,
The reverse mode of the Na(+)/Ca(2+) exchanger provides a source of Ca(2+) for store refilling following agonist-induced Ca(2+) mobilization.
2007,
Pubmed
Jacob,
GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition.
2008,
Pubmed
Makaron,
Cognition-impairing effects of benzodiazepine-type drugs: role of GABAA receptor subtypes in an executive function task in rhesus monkeys.
2013,
Pubmed
Martinez,
Safety of long-acting beta-agonists--an urgent need to clear the air.
2005,
Pubmed
Martinez,
Serious adverse events and death associated with treatment using long-acting beta-agonists.
2006,
Pubmed
Masoli,
The global burden of asthma: executive summary of the GINA Dissemination Committee report.
2004,
Pubmed
McGraw,
Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway beta-agonist paradox.
2003,
Pubmed
Mizuta,
GABAA receptors are expressed and facilitate relaxation in airway smooth muscle.
2008,
Pubmed
Mortensen,
GABA Potency at GABA(A) Receptors Found in Synaptic and Extrasynaptic Zones.
2011,
Pubmed
Olsen,
International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update.
2008,
Pubmed
Peters,
Real-world Evaluation of Asthma Control and Treatment (REACT): findings from a national Web-based survey.
2007,
Pubmed
Qian,
Two distinct pathways for refilling Ca2+ stores in permeabilized bovine trachealis muscle.
1999,
Pubmed
Ramerstorfer,
The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes.
2010,
Pubmed
Richetto,
Behavioral effects of the benzodiazepine-positive allosteric modulator SH-053-2'F-S-CH₃ in an immune-mediated neurodevelopmental disruption model.
2015,
Pubmed
Sieghart,
Subunit composition, distribution and function of GABA(A) receptor subtypes.
2002,
Pubmed
Suissa,
US Food and Drug Administration-mandated trials of long-acting β-agonists safety in asthma: will we know the answer?
2013,
Pubmed
Townsend,
Effects of ginger and its constituents on airway smooth muscle relaxation and calcium regulation.
2013,
Pubmed
Townsend,
Active components of ginger potentiate β-agonist-induced relaxation of airway smooth muscle by modulating cytoskeletal regulatory proteins.
2014,
Pubmed
Townsend,
Quercetin acutely relaxes airway smooth muscle and potentiates β-agonist-induced relaxation via dual phosphodiesterase inhibition of PLCβ and PDE4.
2013,
Pubmed
Xiang,
A GABAergic system in airway epithelium is essential for mucus overproduction in asthma.
2007,
Pubmed
Xiao,
Functional role of canonical transient receptor potential 1 and canonical transient receptor potential 3 in normal and asthmatic airway smooth muscle cells.
2010,
Pubmed
Zurek,
Sustained increase in α5GABAA receptor function impairs memory after anesthesia.
2014,
Pubmed