[Involvement of G proteins between receptors and KCa channels in the regulation of airway tone by the autonomic nervous system].
The mechanical tone of the airways is regulated by the autonomic nervous system, partly via the activity of ion channels. Ca(2+)-activated K+ (KCa) channels are densely distributed on tracheal smooth muscle cells. We found that beta-adrenergic agonists can augment KCa channel activity via the alpha subunit of the stimulatory GTP-binding (G) protein of adenylyl cyclase, Gs, linked with beta-receptors, and that muscarinic agonists can suppress the activity of this channel via the inhibitory G protein of adenylyl cyclase (pertussis toxin-sensitive G protein), Gi, linked with muscarinic receptors. These results show that there is a dual regulation system of KCa channels, which involves stimulation of the two receptors. Records of isometric tension from guinea pig tracheas incubated with pertussis toxin and cholera toxin show that regulation of KCa channels mediated by Gi and Gs may be important in the mechanical antagonism by the two receptor agonists, and they show that G proteins coupling between receptors and KCa channels may be important in beta-adrenergic bronchodilation in the treatment of asthma. In a previous study in eight atopic asthmatic patients, pretreatment with a beta-agonist abolished allergen-induced bronchoconstriction with no increment in mean plasma histamine, results that are similar to those obtained with cromyolyn sodium, a membrane stabilizer. The membrane-delimited reaction may be a key process in the autonomic regulation of airway tone. In immediate asthmatic reactions (IAR), histamine release from mast cells, contraction of airway smooth muscle, and transmitter release from post-ganglionic neurons within parasympathetic ganglia are believed to be caused by membrane hypopolarization. Because activation of KCa channels leads to hyperpolarization, beta-agonists that cause membrane hyperpolarization (short acting beta-agonists) may antagonize IAR at the level of the cell membrane. In late asthmatic reactions (LAR), short-acting beta-agonists do not have marked effects. However, recent reports have indicated that long-acting beta-agonists that do not cause hyperpolarization can inhibit LAR. Cromakalim, an ATP-sensitive K+ channel activator, reduces the "morning dip" when it is given orally to patients with nocturnal asthma. These findings show that activation of K+ channels may be useful in therapy of bronchial asthma.
Kume
H
H
Second Department of Internal Medicine, School of Medicine, Nagoya University, Japan.
Takagi
K
K
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology; D001341:Autonomic Nervous System / Q000502:physiology*; D001980:Bronchi / Q000294:innervation; D002415:Cats; D004285:Dogs; D019204:GTP-Binding Proteins / Q000502:physiology*; D066298:In Vitro Techniques; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000294:innervation; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000502:physiology
D000318:Adrenergic beta-Agonists; D015221:Potassium Channels; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases