Exp Mol Med.  2013 Dec;45(12):e67.

Serotonin contracts the rat mesenteric artery by inhibiting 4-aminopyridine-sensitive Kv channels via the 5-HT2A receptor and Src tyrosine kinase

• Sung DJ
• Noh HJ
• Kim JG
• Park SW
• Kim B
• Cho H
• Bae YM

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.

Keyword

5-HT2A receptor; mesenteric artery; serotonin (5-hydroxytryptamine); voltage-gated K+ channel

MeSH Terms

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
4-Aminopyridine
Calcium Channel Blockers
Calcium Channels
Ketanserin
Nifedipine
Potassium Channel Blockers
Potassium Channels, Voltage-Gated
Protein Kinase Inhibitors
Receptor, Serotonin, 5-HT2A
Serotonin 5-HT2 Receptor Antagonists
Serotonin
src-Family Kinases
Spiperone