Serotonin contracts the rat mesenteric artery by inhibiting 4-aminopyridine-sensitive Kv channels via the 5-HT2A receptor and Src tyrosine kinase.
- Author:
Dong Jun SUNG
1
;
Hyun Ju NOH
;
Jae Gon KIM
;
Sang Woong PARK
;
Bokyung KIM
;
Hana CHO
;
Young Min BAE
Author Information
1. Department of Physiology and the Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea. hanacho@skku.edu
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
5-HT2A receptor;
mesenteric artery;
serotonin (5-hydroxytryptamine);
voltage-gated K+ channel
- MeSH:
4-Aminopyridine/pharmacology;
Action Potentials;
Animals;
Calcium Channel Blockers/pharmacology;
Calcium Channels/metabolism;
Cells, Cultured;
Ketanserin/pharmacology;
Male;
Mesenteric Arteries/drug effects/*metabolism/physiology;
Muscle Contraction;
Muscle, Smooth, Vascular/cytology/drug effects/metabolism/physiology;
Myocytes, Smooth Muscle/drug effects/metabolism/physiology;
Nifedipine/pharmacology;
Potassium Channel Blockers/pharmacology;
Potassium Channels, Voltage-Gated/antagonists & inhibitors/*metabolism;
Protein Kinase Inhibitors/pharmacology;
Rats;
Rats, Sprague-Dawley;
Receptor, Serotonin, 5-HT2A/*metabolism;
Serotonin/*pharmacology;
Serotonin 5-HT2 Receptor Antagonists/pharmacology;
Spiperone/pharmacology;
*Vasoconstriction;
src-Family Kinases/antagonists & inhibitors/*metabolism
- From:Experimental & Molecular Medicine
2013;45(12):e67-
- CountryRepublic of Korea
- Language:English
-
Abstract:
Serotonin (5-hydroxytryptamine (5-HT)) is a neurotransmitter that regulates a variety of functions in the nervous, gastrointestinal and cardiovascular systems. Despite such importance, 5-HT signaling pathways are not entirely clear. We demonstrated previously that 4-aminopyridine (4-AP)-sensitive voltage-gated K+ (Kv) channels determine the resting membrane potential of arterial smooth muscle cells and that the Kv channels are inhibited by 5-HT, which depolarizes the membranes. Therefore, we hypothesized that 5-HT contracts arteries by inhibiting Kv channels. Here we studied 5-HT signaling and the detailed role of Kv currents in rat mesenteric arteries using patch-clamp and isometric tension measurements. Our data showed that inhibiting 4-AP-sensitive Kv channels contracted arterial rings, whereas inhibiting Ca2+-activated K+, inward rectifier K+ and ATP-sensitive K+ channels had little effect on arterial contraction, indicating a central role of Kv channels in the regulation of resting arterial tone. 5-HT-induced arterial contraction decreased significantly in the presence of high KCl or the voltage-gated Ca2+ channel (VGCC) inhibitor nifedipine, indicating that membrane depolarization and the consequent activation of VGCCs mediate the 5-HT-induced vasoconstriction. The effects of 5-HT on Kv currents and arterial contraction were markedly prevented by the 5-HT2A receptor antagonists ketanserin and spiperone. Consistently, alpha-methyl 5-HT, a 5-HT2 receptor agonist, mimicked the 5-HT action on Kv channels. Pretreatment with a Src tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, prevented both the 5-HT-mediated vasoconstriction and Kv current inhibition. Our data suggest that 4-AP-sensitive Kv channels are the primary regulator of the resting tone in rat mesenteric arteries. 5-HT constricts the arteries by inhibiting Kv channels via the 5-HT2A receptor and Src tyrosine kinase pathway.
