Activation of D1-like receptor-dependent phosphatidylinositol signal pathway by SKF83959 inhibits voltage-gated sodium channels in cultured striatal neurons.
Dopamine, a key neurotransmitter mediating the rewarding effects, exerts some of its effects by modulating neuronal excitability of striatal medium spiny neurons. A D1-like dopamine receptor-dependent phosphatidylinositol signal pathway exists in the striatum, however little is known about its role in the dopaminergic modulation of striatal neuronal excitability. 3-Methyl-6-chloro-7, 8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a selective D1 receptor agonist with high-affinity. Here, we observed its effect on the voltage-gated sodium channels (VGSCs) in primary cultured striatal neurons by whole cell patch-clamp technique. We found that SKF83959 induced an inhibition on VGSCs in a dose-dependent manner in striatal neurons (IC50 value: 3.31 ± 0.39 μM), which could be prevented by antagonist of D1 receptor, but not that of D2, α1 adrenergic, or cholinoceptor. The effect of SKF83959 on VGSCs was also prevented by pretreatment with inhibitors of phospholipase C (PLC) and protein kinases C (PKC), but the inositol-1,4,5-phosphate 3 (IP3) antagonist did not occlude SKF83959 (1μM)-induced reduction of VGSCs. These data indicate that SKF83959 inhibits VGSCs in cultured striatal neurons via D1-like receptor-phosphatidylinositol-PKC pathway, which may underlie the dopaminergic modulation on striatal neuronal excitability.
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China.
Jin
J
Ma
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan City, Hubei 430030, China; The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China.
Li-Hong
LH
Long
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan City, Hubei 430030, China.
Zhuang-Li
ZL
Hu
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China.
Hai
H
Zhang
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China.
Jun
J
Han
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan City, Hubei 430030, China.
Lan
L
Ni
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan City, Hubei 430030, China; The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China.
Fang
F
Wang
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan City, Hubei 430030, China; The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China.
Jian-Guo
JG
Chen
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan City, Hubei 430030, China; The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: wupengfeipharm@foxmail.com.
Peng-Fei
PF
Wu
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism*; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
D017447:Receptors, Dopamine D1; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C080703:SK&F 83959; D010738:Type C Phospholipases
Dopamine receptor; Patch-clamp technique; SKF83959; Voltage-gated sodium channels