The tricyclic antidepressant cyproheptadine rescues egg-laying defect of grk-2 mutants

Serotonin regulates egg-laying by activating vulva muscle contraction. Its oxidization metabolite 5-HIAA inhibits vulva muscle contraction. The loss-of-function mutants of grk-2 have strong egg-laying defects because they have serotonin depletion and high level of 5-HIAA. The experiment results show that 5-HIAAs function depends on 5-HT1/HT2 receptor SER-1. The egg-laying inhibition can be completely reverted by loss-of-function goa-1, the Go homolog in C. elegans. Serotonin and 5-HIAA competes for SER-1 binding and they activate different G protein complexes. The tricyclic antidepression drug cyproheptadine can block 5-HIAA function. The experiment results propose a plausible mechanism of cyproheptadine function. On the postsynaptic membrane, SER-1 binding with cyproheptadine can only recruit serotonin, thus, it biased activates Gq instead of Go coupled signaling.