Cyclic ADP ribose coupled to 5-HT receptors in glial cells

Abstract

Human serotonin 5A (5-HT_5A) receptors couple to multiple signaling cascades including the inhibition of cADPR. When the 5-HT_5A receptors were expressed in undifferentiated C6 glioma cells, activation of 5-HT_5A receptors inhibited ADP-ribosyl cyclase and cyclic ADP ribose formation via Gi/Go. Cyclic ADPR is produced from NAD+ by ADP-ribosyl cyclase and targets type-II ryanodine receptors to release Ca²⁺. Therefore, cADPR is suggested as an intracellular Ca²⁺ modulating second messenger. The formation of cADPR is regulated by the phosphorylation of ADP-ribosyl cyclase, dependent on either cAMP- or cGMP-dependent protein kinase. Since inhibition of adenylyl cyclase activity and cAMP accumulation by 5-HT_5A receptors was observed, cAMP-dependent protein kinase was predicted to be also inhibited which in turn might attenuate ADP-ribosyl cyclase activity. Therefore, the dual inhibitions of ADP-ribosyl cyclase due to both direct and indirect effect of 5-HT_5A receptors may affect cellular functions related to cADPR. On the contrary, activation of 5-HT_5A receptors transiently opened the K⁺ channels, presumably due to the increase in intracellular Ca²⁺ after formation of inositol (1,4,5) trisphosphate. Taking these competing actions on Ca²⁺ signaling, 5-HT_5A receptors are likely to tune the intracellular Ca²⁺ level. In fact, 5-HT-induced outward K⁺ currents were significantly augmented by cyclosporine, an inhibitor of ryanodine receptor-induced Ca²⁺ mobilization. Impairment of these multiple signaling might therefore cause complex disabilities, leading to the various psychological disorders. [Jpn J Physiol 54 Suppl:S17 (2004)]