The effect of DA-9701 on 5-hydroxytryptamine-induced contraction of feline esophageal smooth muscle cells.
Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter found in blood platelets, the gastrointestinal (GI) tract, and the central nervous system (CNS) of animals and humans. The signaling pathways of 5-hydroxytryptamine (5-HT)-induced contractions in cat esophageal smooth muscle cell (ESMC)s have been identified, but the downstream components of the 5-HT signaling pathway remain unclear. DA-9701 is the standardized extract of the Pharbitis nil Choisy seed (Pharbitidis Semen, Convolvulaceae) and the root of Corydalis yahusuo W.T. Wang (Corydalis Tuber, Papaveraceae). DA-9701 is known to have strong gastroprokinetic effects and a good safety profile. In this study, we investigated the 5-HT signaling pathway at the G-protein level, and we explored the mechanisms by which DA-9701 induces smooth muscle contraction. Freshly isolated smooth muscle cells were harvested from the feline esophagus, and cells were permeabilized to measure their length. 5-HT produced esophageal smooth muscle contractions in a dose-dependent manner. Furthermore, 5-HT produced a relatively long-acting contraction. 5-HT binds to the 5-HT2, 5-HT3 and 5-HT4 receptors to induce smooth muscle contraction in feline ESMCs. These receptors, which are located in esophageal smooth muscle, are coupled to Gαq, Gαo and Gαs. These G proteins activate PLC, which leads to Ca2+/calmodulin-dependent MLCK activation, resulting in MLC20 phosphorylation and cell contraction. Conversely, DA-9701 inhibits 5-HT-induced contraction by inhibiting MLC20 phosphorylation.
Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea. okhboss@hanmail.net.
Kyung Hoon
KH
Oh
Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea. yoonnamjin@naver.com.
Yoonjin
Y
Nam
Department of Pharmacology, School of Medicine, Chung-Ang University, Seoul 156-756, Korea. jhjeong3@cau.ac.kr.
Ji Hoon
JH
Jeong
Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Korea. inkim@knu.ac.kr.
In Kyeom
IK
Kim
Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea. udsohn@cau.ac.kr.
Uy Dong
UD
Sohn
D000818:Animals; D002415:Cats; D004947:Esophagus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects* / Q000235:genetics; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D028321:Plant Preparations / Q000494:pharmacology*; D011485:Protein Binding; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
C533973:DA-9701; D005765:Gastrointestinal Agents; D018994:Myosin Light Chains; D028321:Plant Preparations; D011985:Receptors, Serotonin; D012701:Serotonin; D009219:Myosin-Light-Chain Kinase; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins