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SOMATOSTATIN RECEPTO Sintesi della relazione

Project ID: QLG3-CT-1999-00908
Finanziato nell'ambito di: FP5-LIFE QUALITY
Paese: Germany

Map of sst subtype co-localization with neurotransmitters

The interaction of somatostatin with other neurotransmitters may reveal therapeutic targets. To further extent our previous observation of the spatial relationship of the somatostatin signalling system and the biogenic amines we now investigated the co-localization of somatostatin receptors and tryptophane hydroxylase (TPH), a marker for serotonergic neurotransmission. The cell bodies of serotonergic neurons are located in the brain stem restricted to 9 discrete cell clusters (B1-B9) within the raphe nuclei and adjacent nuclear groups. Therefore, we examined these brain regions using an immunohistochemical double labelling method to detect cells, co-expressing sst subtypes and TPH.

Our results demonstrate that TPH positive cells have the highest degree of co-localization with sst2B immunoreactivity in neurons of the cell groups B1-B9. Still about 46% of sst1 and TPH-positive cells co-localize in the cell groups B1-B9 and nearly the same level of co-localization was detected for sst4 and TPH-positive cells in the cell groups B1-B3 and B9. Lower numbers of sst4 and TPH co-expressing cells were detected in cell clusters B5+B8, B6+B7, B7_CG and B4. A low degree of co-localization was also detected for sst2A and TPH expressing cells located in brain regions B3, B9, B2, B1 and B5+B8. Very low numbers of co-expressing cells were detected in the cell clusters B6+B7. In region B7_CG no sst2A and TPH co-expressing cells were observed. A minimal co-localization of sst3 and TPH immunoreactivity was detected in the cell clusters B3 and B7_CG. No double labelled cells were found in the regions B4, B5+B8, B6+B7 and in the cell groups B1_RPa, B1_CVL, B2 and B9 even no sst3 positive neuronal cilia were observed. Our data suggest that interactions between the somatostatinergic and the serotonergic systems mainly involve the receptor subtypes sst2B, sst1, sst4 and to a lower extend sst2A, whereas sst3 seems not to play an important role in this interaction.

Another site where we studied functional interaction of somatostatin with other signalling systems was the rat hypothalamus, a major site regulating feeding behaviour. During the last reporting period we have shown that in many hypothalamic regions somatostatin receptor subtypes are expressed in leptin-responsive neurons. We now have addressed the functional importance of this co-localization by icv administration of leptin and somatostatin to experimental rats in comparison to control animals. By western blotting experiments using hypothalamic protein extracts we demonstrated that somatostatin and sst1, sst2 or sst3 selective agonists inhibited leptin mediated phosphorylation of the signalling molecule STAT3, while an sst4 selective agonist was ineffective.

We also examined the effect of somatostatin agonists histochemically on the leptin-induced nuclear translocation of STAT3 in hypothalamic nuclei known to participate in feeding regulation. Somatostatin inhibited STAT3 translocation significantly in the ventromedial hypothalamic nucleus (VMH), the lateral hypothalamic area (LHA) and the dorsomedial hypothalamic nuclus (DMH) to various extents. It did not significantly so in the arcuate nucleus (ARC). These effects were also seen with sst3 agonists and could be attenuated by an sst3 antagonists. Sst1 and sst2 agonists showed still significant, but weaker effects in the aforementioned nuclei. In addition they could also block STAT3 in the ARC. As a behavioural correlate we also measured inhibition of leptin’s anorectic effect by somatostatin agonists. It turned out that somatostatin itself and sst1, sst2 and sst3 agonists were effective while sst4 agonists did not elicit an effect. These data suggest that somatostatin is a modulator of leptin’s anorectic action.

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Wolfgang MEYERHOF, (Head of department)
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