Serotonin Reduces the Hyperpolarization-Activated Current (Ih) in Ventral Tegmental Area Dopamine Neurons: Involvement of 5-HT2 Receptors and Protein Kinase C

2003 ◽  
Vol 90 (5) ◽  
pp. 3201-3212 ◽  
Author(s):  
Zhaoping Liu ◽  
E. Bradshaw Bunney ◽  
Sarah B. Appel ◽  
Mark S. Brodie
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ventral Tegmental Area ◽  
Kinase Inhibitor ◽  
Brain Slices ◽  
Dopamine Neurons ◽  
Dependent Manner ◽  
Cationic Current ◽  
Kinase C ◽  
Ventral Tegmental

Dopaminergic neurons of the ventral tegmental area (VTA) have been implicated in the rewarding properties of drugs of abuse and in the etiology of schizophrenia; serotonin modulation of these neurons may play a role in these phenomena. Whole cell patch-in-the-slice recording in rat brain slices was used to investigate modulation of the hyperpolarization-activated cationic current Ih by serotonin in these neurons. Serotonin (50-500 μM) reduced the amplitude of Ih in a concentration-dependent manner; this effect was reversible after prolonged washout of serotonin. This effect was mimicked by the 5-HT2 agonist α-methylserotonin (25 μM) and reversed by the 5-HT2 antagonist ketanserin (25 μM). Serotonin reduced the maximal Ih current and conductance (measured at -130 mV) and caused a negative shift in the voltage dependence of Ih activation. The serotonin-induced reduction in Ih amplitude was antagonized by intracellular administration of the nonspecific protein kinase inhibitor H-7 (75 μM) and the selective protein kinase C inhibitor chelerythrine (25 μM). The protein kinase C activator phorbol 12, 13 diacetate (PDA, 2 μM) reduced Ih amplitude; when PDA and serotonin were applied together, the effect on Ih was less than additive. These data support the conclusion that serotonin reduces Ih in dopaminergic VTA neurons by acting at serotonin 5-HT2 receptors, which activate protein kinase C. This reduction of Ih may be physiologically important, as the selective inhibitor of Ih, ZD7288, significantly increased dopamine inhibition of firing rate of dopaminergic VTA neurons, an effect that we previously demonstrated with serotonin.

Orexin-a activates phospholipase C- and protein kinase C-mediated Ca2+ signaling in dopamine neurons of the ventral tegmental area

Neuroreport ◽  
2001 ◽  
Vol 12 (9) ◽  
pp. 1885-1889 ◽  
Author(s):  
Kazuhide Uramura ◽  
Hisayuki Funahashi ◽  
Shinji Muroya ◽  
Seiji Shioda ◽  
Morikuni Takigawa ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ventral Tegmental Area ◽  
Phospholipase C ◽  
Dopamine Neurons ◽  
Orexin A ◽  
Kinase C ◽  
Ventral Tegmental

scholarly journals Staurosporine, a Novel Protein Kinase C Inhibitor, Prevents Postischemic Neuronal Damage in the Gerbil and Rat

1990 ◽  
Vol 10 (5) ◽  
pp. 646-653 ◽  
Author(s):  
Hideaki Hara ◽  
Hiroshi Onodera ◽  
Mikio Yoshidomi ◽  
Yuzuru Matsuda ◽  
Kyuya Kogure
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Neuronal Damage ◽  
Pyramidal Cells ◽  
Protein Kinase Inhibitors ◽  
Dependent Manner ◽  
Dependent Protein Kinase ◽  
Kinase C ◽  
Dependent Protein

The protective effects of protein kinase inhibitors and a calmodulin kinase inhibitor (W-7) against ischemic neuronal damage were examined in the CA1 subfield of the hippocampus. Staurosporine, KT5720, and KT5822 were used as inhibitors of protein kinase C (PKC), cyclic AMP–dependent protein kinase, and cyclic GMP–dependent protein kinase, respectively. All test compounds were injected topically into the CA1 subfield of the hippocampus. In the gerbil ischemia model, staurosporine (0.1–10 ng) administered 30 min before ischemia prevented neuronal damage in a dose-dependent manner. However, KT5720, KT5822, and W-7 were ineffective, even at a dose of 10 ng. In the rat ischemia model, staurosporine (10 ng) also prevented neuronal damage when administered before ischemic insult, although staurosporine administered 10 or 180 min after recirculation was ineffective. These results suggest the involvement of PKC in CA1 pyramidal cell death after ischemia and that the fate of vulnerable CA1 pyramidal cells through PKC-mediated processes could be determined during the early recirculation period.

CCK activates p90rsk in rat pancreatic acini through protein kinase C

1997 ◽  
Vol 272 (3) ◽  
pp. G401-G407 ◽  
Author(s):  
M. J. Bragado ◽  
A. Dabrowski ◽  
G. E. Groblewski ◽  
J. A. Williams
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Threshold Concentration ◽  
Mitogen Activated Protein Kinase ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Pancreatic Acini ◽  
Kinase C ◽  
Mitogen Activated Protein

The presence of the 90-kDa ribosomal S6 protein kinase (p90(rsk)) in isolated rat pancreatic acini was demonstrated by Western blotting and immunoprecipitation with anti-p90(rsk). Cholecystokinin (CCK) activated p90(rsk) activity in a time- and dose-dependent manner and increased its phosphorylation. The threshold concentration of CCK was 10 pM and the maximal effect was seen at 1 nM. An increase in p90(rsk) was observed 1 min after 1 nM CCK stimulation, reaching a maximum at 10 min, when p90(rsk) activity was increased 5.4-fold. Carbachol and bombesin, but not vasoactive intestinal peptide, also activated p90(rsk). CCK-induced activation of p90(rsk) appears to be mediated by protein kinase C (PKC), since 12-O-tetradecanoylphorbol-13-acetate increased p90(rsk) activity 5.3-fold. GF-109293X, a potent inhibitor of PKC, strongly inhibited CCK-evoked p90(rsk) activity. Treatment of acini with ionomycin or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid had no effect, indicating that mobilization of intracellular Ca2+ by CCK is not important in p90(rsk) activation. Although there were some quantitative differences in the extent of inhibition, the specific inhibitors [rapamycin, wortmannin, mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059, and GF-109293X] had parallel effects on p90(rsk) and p42(mapk) activities, consistent with a model in which p90(rsk) can be regulated in acini by MAPK.

Rho kinase mediates serum-induced contraction in fibroblast fibers independent of myosin LC20 phosphorylation

2003 ◽  
Vol 284 (3) ◽  
pp. C599-C606 ◽  
Author(s):  
Hiromi Nobe ◽  
Koji Nobe ◽  
Fabeha Fazal ◽  
Primal de Lanerolle ◽  
Richard J. Paul
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Light Chain ◽  
Kinase Inhibitor ◽  
Calf Serum ◽  
Rho Kinase ◽  
Fiber Formation ◽  
Dependent Manner ◽  
Sustained Contraction ◽  
Kinase C

Fibroblasts form fibers when grown in culture medium containing native type 1 collagen. The contractile forces generated can be precisely quantified and used to analyze the signal transduction pathways regulating fibroblast contraction. Calf serum (30%) induces a sustained contraction that is accompanied by a transient increase in intracellular calcium ([Ca2+]i). W-7, a calmodulin inhibitor, KN-62, an inhibitor of calcium/calmodulin-dependent protein kinase, and ML-7, a myosin light-chain kinase inhibitor, had no effects on either the contraction or the [Ca2+]i responses. Neither genistein, a tyrosine kinase inhibitor, nor calphostin C, a protein kinase C inhibitor, had major effects on force or [Ca2+]i. In contrast, the Rho kinase inhibitors (R)-(+)- trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632) and HA1077 depressed the contraction in a dose-dependent manner without affecting the [Ca2+]iresponse. Stress fiber formation was also suppressed by Y-27632. Surprisingly, calf serum, Y-27632, and calf serum plus Y-27632 did not alter mono- or diphosphorylation of the myosin regulatory light chain (MRLC) compared with control untreated fibers. These results suggest that the sustained contraction of NIH 3T3 fibroblast fibers induced by calf serum is mediated by Rho kinase but is independent of a sustained increase in [Ca2+]i, calcium/calmodulin- or protein kinase C-dependent pathways, or increases in MRLC phosphorylation.

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