Serotonin inhibits voltage-gated K+ currents in pulmonary artery smooth muscle cells: role of 5-HT2A receptors, caveolin-1, and KV1.5 channel internalization.
Multiple lines of evidence indicate that serotonin (5-hydroxytryptamine [5-HT]) and voltage-gated K+ (KV) channels play a central role in the pathogenesis of pulmonary hypertension (PH). We hypothesized that 5-HT might modulate the activity of KV channels, therefore establishing a link between these pathogenetic factors in PH. Here, we studied the effects of 5-HT on KV channels present in rat pulmonary artery smooth muscle cells (PASMC) and on hKV1.5 channels stably expressed in Ltk- cells. 5-HT reduced native KV and hKV1.5 currents, depolarized cell membrane, and caused a contraction of isolated pulmonary arteries. The effects of 5-HT on KV currents and contraction were markedly prevented by the 5-HT2A receptor antagonist ketanserin. Incubation with inhibitors of phospholipase C (U73122), classic protein kinase Cs (Gö6976), or tyrosine kinases (genistein and tyrphostin 23), the cholesterol depletion agent beta-cyclodextrin or concanavalin A, an inhibitor of endocytotic processes, also prevented the effects of 5-HT. In homogenates from pulmonary arteries, 5-HT2A receptors and caveolin-1 coimmunoprecipitated with KV1.5 channels, and this was increased on stimulation with 5-HT. Moreover, KV1.5 channels were internalized when cells were stimulated with 5-HT, and this was prevented by concanavalin A. These findings indicate that activation of 5-HT2A receptors inhibits native KV and hKV1.5 currents via phospholipase C, protein kinase C, tyrosine kinase, and a caveolae pathway. KV channel inhibition accounts, at least partly, for 5-HT-induced pulmonary vasoconstriction and might play a role in PH.
Cogolludo
Angel
A
Department Pharmacology, School Medicine, Universidad Complutense, Madrid, Spain. acogolludo@ift.csic.es
Moreno
Laura
L
Lodi
Federica
F
Frazziano
Giovanna
G
Cobeño
Laura
L
Tamargo
Juan
J
Perez-Vizcaino
Francisco
F
D000818:Animals; D051242:Caveolin 1 / Q000187:drug effects / Q000502:physiology*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D007650:Ketanserin / Q000494:pharmacology; D051666:Kv1.5 Potassium Channel / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*
D051242:Caveolin 1; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D044402:Receptor, Serotonin, 5-HT2A; D012701:Serotonin; D007650:Ketanserin