Serotonin is a conserved neuromodulator that is involved in numerous physiological processes and functional states, including feeding, thermoregulation, cognition, and affect. Although much is known about how serotonin acts on its cellular targets, how its release is regulated in vivo remains poorly understood. In the nematode C. elegans, female reproductive behavior depends on a pair of serotoninergic motor neurons, which are directly modulated by inhibitory neuropeptides. Here, I report the isolation of mutants in which inhibitory neuropeptides fail to properly modulate serotonin neurons and the behavior they mediate. One of the corresponding mutations affects the T-type calcium channel CCA-1 and symmetrically re-tunes the voltage-dependencies of its activation and inactivation towards more hyperpolarized potentials. This shift in voltage dependency strongly and specifically bypasses the effects of peptidergic inhibition on serotonin neurons. The other corresponding mutation isolated from this screen likely affects the two-pore potassium channel TWK-17. The putative TWK-17 mutation restores activity to serotonin neurons that have been shut down due to excess peptidergic inhibition. My results indicate that manipulations of these two types of ion channels can restore function to hypo-active neurons and may demonstrate conserved mechanisms governing serotonin release.
|Commitee:||Burden, Steven J., Chesler, Mitchell, Hubbard, E. Jane|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 79/08(E), Dissertation Abstracts International|
|Keywords:||K2P channel, LVA channels, Serotonin, Serotonin release, T-type calcium channels, Two-pore potassium channels|
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