[Molecular mechanisms for cAMP-independent activation of MaxiK channel: G protein direct channel regulation and contribution to the tuning of vascular smooth muscle tone].
MaxiK channel, the large conductance Ca(2+)-sensitive K+ channel, is expressed abundantly in vascular smooth muscles and plays a key role in the tuning of their excitability and contractility. The present study was carried out to elucidate the contribution of MaxiK channel to prostacyclin receptor (IP receptor)-mediated vascular relaxation with a special reference to the role of cAMP. An IP agonist, beraprost, induced a strong relaxation in de-endothelialized guinea pig thoracic aorta, which was almost abolished by a MaxiK channel selective blocker, iberiotoxin (IbTx). Beraprost produced a 30-fold rise in tissue cAMP contents. In addition, beraprost-induced relaxation potentiated in the presence of Ro-20-1724 (a selective inhibitor of cAMP-specific phosphodiesterase) was completely counteracted by IbTx. However, beraprost-induced relaxation was not affected by SQ22,536, an adenylyl cyclase inhibitor, which abolished this IP agonist-induced elevation of cAMP contents. SQ22,536-insensitive relaxant component was significantly inhibited by IbTx. Cholera toxin, a Gs activator, qualitatively mimicked the effects of beraprost. Furthermore, MaxiK channel currents in aortic myocytes were increased by beraprost in a GTP-dependent manner. These results indicate that both cAMP-dependent and -independent pathways contribute to MaxiK channel-mediated vascular relaxation following IP receptor stimulation. Direct regulation by Gs seems to partly account for MaxiK channel-mediated, cAMP-independent mechanism.
Yamaki
Fumiko
F
Departments of Chemical Pharmacology and Pharmacology, Toho University School of Pharmaceutical Sciences, Miyama 2-2-1, Funabashi-City, Chiba 274-8510, Japan.
Tanaka
Yoshio
Y
Horinouchi
Takahiro
T
Shigenobu
Koki
K
Koike
Katsuo
K
D000818:Animals; D000242:Cyclic AMP / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D044006:Receptors, Epoprostenol / Q000502:physiology; D014664:Vasodilation / Q000502:physiology*
D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D044006:Receptors, Epoprostenol; D000242:Cyclic AMP; D019204:GTP-Binding Proteins