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Increased inhibitory activity of protein kinase C on the serotonin transporter in OCD
D Marazziti1, I Masala, A Rossi
1Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Italy. dmarazzi@psico.med.unipi.it
Abstract:
Different observations show a reduced functionality of the serotonin (5-HT) transporter in obsessive-compulsive disorder (OCD) that might be due to a disturbance of its regulation at intracellular level. Protein kinase C (PKC) has been reported to provoke a decrease in the number of the 5-HT transporter proteins. Therefore, we investigated whether OCD patients differed from control subjects in the effect of PKC upon the 5-HT transporter, after stimulation of this enzyme with 4beta-12-tetradecanoylphorbol 13-acetate (beta-TPA). Fifteen patients affected by OCD, according to DSM-IV criteria, were compared with a similar group of healthy subjects. The determination of 5-HT uptake was carried out according to the method of Arora and Meltzer with slight modifications. At baseline, OCD patients showed a significant decrease in the maximal velocity (V(max)) of 5-HT uptake, as compared with control subjects, with no change in the Michaelis-Menten constant (K(m)). The activation of PKC with beta-TPA provoked a significant decrease in V(max) values in both groups, but the effect was significantly more robust in OCD patients who, in turn, also showed also an increase in K(m) values. These findings could indicate the presence of hyperactivity of PKC in OCD that could be the result of increased activity of the phosphatidylinositol pathway. In addition, this suggests new potential therapeutic targets in OCD.
Insights
Obsessive-compulsive disorder (OCD) patients exhibit reduced serotonin transporter (5-HT) functionality. Protein kinase C (PKC) activation exacerbates this deficit, suggesting PKC hyperactivity in OCD and potential new therapeutic targets.
Area of Science:
- Neuroscience
- Biochemistry
- Psychiatry
Background:
- Reduced serotonin transporter (5-HT) functionality is observed in obsessive-compulsive disorder (OCD).
- Protein kinase C (PKC) may downregulate 5-HT transporter expression.
- Intracellular regulatory disturbances are hypothesized in OCD's 5-HT transporter dysfunction.
Purpose of the Study:
- To investigate differences in PKC's effect on the 5-HT transporter between OCD patients and healthy controls.
- To examine the impact of PKC activation via beta-TPA on 5-HT transporter kinetics in OCD.
Main Methods:
- Compared 15 DSM-IV diagnosed OCD patients with matched healthy controls.
- Measured 5-HT uptake kinetics (Vmax and Km) using a modified Arora and Meltzer method.
- Stimulated PKC activity using 4beta-12-tetradecanoylphorbol 13-acetate (beta-TPA).
Main Results:
- OCD patients showed significantly lower baseline Vmax for 5-HT uptake compared to controls.
- PKC activation with beta-TPA significantly decreased Vmax in both groups.
- The decrease in Vmax was more pronounced in OCD patients, who also exhibited increased Km values after beta-TPA stimulation.
Conclusions:
- Findings suggest hyperactivity of PKC in OCD patients.
- Increased phosphatidylinositol pathway activity may underlie PKC hyperactivity in OCD.
- These results indicate potential novel therapeutic targets for OCD treatment.