Converging evidence has suggested that anandamide (AEA), an endogenous agonist of cannabinoid (CB) receptors, can directly interact with certain types of ligand-gated ion channels (LGICs). However, little is known about the molecular and cellular mechanisms of AEA-induced direct effects on LGICs. Here, we report that AEA inhibited the function of serotonin-gated ion channels (5-HT3A) expressed in Xenopus laevis oocytes and human embryonic kidney 293 cells in a manner that was dependent on the steady-state receptor density at the cell surface. The magnitude of AEA inhibition was inversely correlated with the expression levels of receptor protein and function. With increasing surface receptor expression, the magnitude of AEA inhibition decreased. Consistent with this idea, pretreatment with actinomycin D, which inhibits transcription, decreased the amplitude of current activated by maximal concentrations of 5-hydroxytryptamine (5-HT) and increased the magnitude of AEA inhibition. AEA did not significantly alter 5-HT3A receptor trafficking. However, AEA accelerated 5-HT3A receptor desensitization time in a concentration-dependent manner without significantly changing receptor activation and deactivation time. The desensitization time was correlated with the AEA-induced inhibiting effect and mean 5-HT current density. Applications of 5-hydroxyindole and nocodazole, a microtubule disruptor, significantly slowed 5-HT3A receptor desensitization and reduced the magnitude of AEA inhibition. These observations suggest that 5-HT3 receptor density at the steady state regulates receptor desensitization kinetics and the potency of AEA-induced inhibiting effect on the receptors. The inhibition of 5-HT3 receptors by AEA may contribute to its physiological roles in control of pain and emesis.
|Number of pages||9|
|Publication status||Published - Feb 2008|
All Science Journal Classification (ASJC) codes
- Molecular Medicine