| Title | Somatodendritic autoreceptor regulation of serotonergic neurons: dependence on L-tryptophan and tryptophan hydroxylase-activating kinases. | | Author(s) | Liu RJ, Lambe EK, Aghajanian GK | | Institution | Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. Rong-Jian.Liu@yale.edu | | Source | Eur J Neurosci 2005 Feb; 21(4):945-58. | | MeSH | 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
Adrenergic alpha-Agonists
Animals
Autoreceptors
Biopterin
Comparative Study
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Inhibitors
Immunohistochemistry
In Vitro
Male
Membrane Potentials
Neurons
Patch-Clamp Techniques
Phenylephrine
Piperazines
Pyridines
Raphe Nuclei
Rats
Research Support, U.S. Gov't, P.H.S.
Serotonin
Serotonin Antagonists
Time Factors
Tryptophan
Tryptophan Hydroxylase
| | Abstract | The somatodendritic 5-HT(1A) autoreceptor has been considered a major determinant of the output of the serotonin (5-HT) neuronal system. However, recent studies in brain slices from the dorsal raphe nucleus have questioned the relevance of 5-HT autoinhibition under physiological conditions. In the present study, we found that the difficulty in demonstrating 5-HT tonic autoinhibition in slice results from in vitro conditions that are unfavorable for sustaining 5-HT synthesis. Robust, tonic 5-HT(1A) autoinhibition can be restored by reinstating in vivo 5-HT synthesizing conditions with the initial 5-HT precursor l-tryptophan and the tryptophan hydroxylase co-factor tetrahydrobiopterin (BH(4)). The presence of tonic autoinhibition under these conditions was revealed by the disinhibitory effect of a low concentration of the 5-HT(1A) antagonist WAY 100635. Neurons showing an autoinhibitory response to L-tryptophan were confirmed immunohistochemically to be serotonergic. Once conditions for tonic autoinhibition had been established in raphe slice, we were able to show that 5-HT autoinhibition is critically regulated by the tryptophan hydroxylase-activating kinases calcium/calmodulin protein kinase II (CaMKII) and protein kinase A (PKA). In addition, at physiological concentrations of L-tryptophan, there was an augmentation of 5-HT(1A) receptor-mediated autoinhibition when the firing of 5-HT cells activated with increasing concentrations of the alpha(1) adrenoceptor agonist phenylephrine. Increased calcium influx at higher firing rates, by activating tryptophan hydroxylase via CaMKII and PKA, can work together with tryptophan to enhance negative feedback control of the output of the serotonergic system. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 15787701 |
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