Cell-type specific coupling of the 5-HT1a-receptor

The 5-HT1a-receptor is considered to be a main target for the action of antidepressants. But it is unclear if this receptor is involved in the enhancement of neuroplasticity by antidepressants. One of the key elements in pro-plastic signaltransduction cascades is the cyclic AMP-response element binding protein (CREB) whose phosphorylation is increased by antidepressants. We demonstrate that in lymphocytic cells (Jurkat) the antidepressant-induced increase of CREB-phosphorylation is inhibited by the 5-HT1a antagonist WAY 100635 but not the 5-HT2a antagonist ketanserin. Furthermore the 5-HT1a agonist 8-OH-DPAT is a potent inductor of CREB-phosphorylation in this cell-type. In neuronal cells (N2A) we find the opposite effect: Antagonising the 5-HT1a-receptor increases CREB-phosphorylation and stimulation decreases it. Ongoing experiments are indicating that these differential effects are due to different coupling of the receptor. The coupling to the MAP-kinase pathway yields an increase of CREB-phosphorylation. The coupling to inhibitory G-proteins seems to inhibit the cAMP-dependent kinases and therefore decreasing CREB-phosphorylation. It remains to be elucidated how this cell-type specific coupling of the 5-HT1a-receptor is determined on the molecular level. Our results suggest that pro-plastic effects mediated by the 5-HT1a-receptor are limited to cell-types with a strong coupling to the MAP-kinase pathway.