Program of the 2001 International Worm Meeting - Sternberg Lab ...

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680. Neurotransmitter transporter
genes in C. elegans.
Gregory P. Mullen, Gary Moulder,
Robert Barstead, Jim Rand
Program in Molecular and Cell Biology,
Oklahoma Medical Research Foundation,
Oklahoma City, OK 73104 USA.
With the wealth of genomic sequence data now
available, it is possible to begin the analysis of
biological phenomena on a genome-wide scale.
A particularly intriguing observation is that
many genes are members of gene families (sets
of genes whose products have closely related
structures and/or functions). One such gene
family encodes the neurotransmitter transporters
and structurally related proteins (the sodium:
neurotransmitter symporter family
(SNF)). These proteins are required for the
efficient clearance of neurotransmitters (and
other bioactive molecules) from synaptic clefts.
Several of these transporters have
well-established roles in behavior and/or
neurological disorders. In addition, they are
known targets for drugs of psychiatric
importance, such as antidepressants, or drugs of
abuse, such as cocaine and amphetamines.
However, for many, the endogenous substrate
and/or cellular functions are unknown. There
are at least 18 members of the SNF family in
humans and 14 each in D. melanogaster and C.
elegans. Sequence comparisons suggest that
humans, fruitflies, and nematodes share a core
set of SNF proteins, which include the
dopamine, serotonin, and GABA transporters.
In addition, they each have unique set of SNF
proteins that is distinct for each organism. In C.
elegans, there are genes that appear to
correspond directly to mammalian dopamine
(dat-1; see abstract by Duerr et al.), serotonin
(mod-5; Ranganathan et al., 2000) and GABA
transporters, as well as a number of orphan
transporters (MacGregor et al., 1997 IWM:377;
James et al., 1999 IWM:436). We now have
gene knockouts in five SNF genes (in addition
to mod-5 and dat-1) and have begun a
systematic analysis of their behavioral
phenotypes. Thus far, our observations indicate
that transporter gene knockouts generally result
in mild behavioral phenotypes. We speculate
that the mild phenotypes associated with these
mutations reflect functional overlaps between
genes ("redundancy") or compensatory
mechanisms for the degradation/recycling of
neurotransmitters.
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