Originally published as Genetics Published Articles Ahead of Print on April 19, 2006.

Genetics, Vol. 173, 111-130, May 2006, Copyright © 2006
doi:10.1534/genetics.105.054007

The Dunce cAMP Phosphodiesterase PDE-4 Negatively Regulates G{alpha}s-Dependent and G{alpha}s-Independent cAMP Pools in the Caenorhabditis elegans Synaptic Signaling Network

Nicole K. Charlie, Angela M. Thomure, Michael A. Schade and Kenneth G. Miller1

Program in Molecular, Cell and Developmental Biology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104

1 Corresponding author: Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104.
E-mail: millerk{at}omrf.ouhsc.edu

Forward genetic screens for mutations that rescue the paralysis of ric-8 (Synembryn) reduction-of-function mutations frequently reveal mutations that cause hyperactivation of one or more components of the G{alpha}s pathway. Here, we report that one of these mutations strongly reduces the function of the Dunce cAMP phosphodiesterase PDE-4 by disrupting a conserved active site residue. Loss of function and neural overexpression of PDE-4 have profound and opposite effects on locomotion rate, but drug-response assays suggest that loss of PDE-4 function does not affect steady-state acetylcholine release or reception. Our genetic analysis suggests that PDE-4 regulates both G{alpha}s-dependent and G{alpha}s-independent cAMP pools in the neurons controlling locomotion rate. By immunostaining, PDE-4 is strongly expressed throughout the nervous system, where it localizes to small regions at the outside boundaries of synaptic vesicle clusters as well as intersynaptic regions. The synaptic subregions containing PDE-4 are distinct from those containing active zones, as indicated by costaining with an antibody against the long form of UNC-13. This highly focal subsynaptic localization suggests that PDE-4 may exert its effects by spatially regulating intrasynaptic cAMP pools.




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